Anticancer Effects of Disulfiram: A Systematic Review of in Vitro, Animal, and Human Studies

Anticancer Effects of Disulfiram: A Systematic Review of in Vitro, Animal, and Human Studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Methodology Anticancer Effects of Disulfiram: A Systematic Review of in Vitro, Animal, and Human Studies ling wang, yang yu, cong zhou, run wan, Yumin Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-140063/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background and objectives: Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Several preclinical and clinical studies have examined the potential of repurposing disulfiram (DSF) as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in in vitro and in vivo models, as well as in humans. Methods: Two authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible in vitro studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics. Results: Overall, 35 studies, i.e., 21 performed in vitro , 11 based on animal models, and three clinical trials, were finally included. In vitro and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule. Conclusions: This systematic review provides evidence regarding the anti-tumor activity of DSF in vitro , in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research. Health Economics & Outcomes Research Scientific Communication disulfiram apoptosis rate tumor inhibition rate progression-free survival overall survival Figures Figure 1 Introduction Cancer is expected to be the leading cause of death and the foremost contributor to decreased life expectancy in every country worldwide during the 21st century and beyond. Although comprehensive therapies prolong survival and improve the quality of life of cancer patients, approximately 96,000,000 cancer deaths occurred in 2018 (Bray et al. 2018). The global community is well aware that new drug development, discovery, and synthesis is a time-consuming process, which involves intensive work and appraisal of the cost-effectiveness of the drug under development (Kaitin et al. 2010). As a result, researchers are allocating considerable efforts for repurposing existing drugs such as disulfiram (DSF). In the 1800s, DSF was used as an industrial catalyst in the production of rubber (Suh et al. 2006). In 1948, DSF was approved by the Food and Drug Administration for treating alcoholism (Eneanya et al. 1981). In 1988, DSF was associated with a decrease in the occurrence of occasional infections in symptomatic patients with human immunodeficiency virus infection (Gotzsche et al. 1988), prompting the conduct of a wealth of clinical trials, some of which are still ongoing ( www.clinicaltrials.gov ). The antineoplastic activity of DSF was first recorded in 1977 by Dr. Lewison in a 35-year-old female breast cancer patient with systemic metastases who received DSF for her severe alcoholic syndrome and remained clinically free of cancer for 10 years without receiving any form of anticancer therapy (Lewison et al. 1977). This observation was noted in an era in which the anticancer effect of DSF was being researched. In recent years, a large number of preclinical studies and clinical trials ( www.clinicaltrials.gov ) of DSF have been conducted to explore the anticancer activities of this drug. Nonetheless, the antitumor effectiveness of DSF remains uncertain owing to existing heterogeneity across different studies with cell lines, animals, and humans. Currently, a systematic review of these studies to assess and clarify the anticancer potential of DSF is lacking. It is worthy to explore whether there are substantial differences and are appropriate for clinical proposals. Therefore, this study aimed to perform a systematic review of published data on the antitumor activity of DSF. Specifically, this review aimed to assess the apoptosis and tumor inhibition rates of DSF based on data from studies in cell lines and animal models, respectively, and examine the benefit of DSF on progression-free survival (PFS) and overall survival (OS) based on results from clinical studies, regardless of the study design or type of cancer investigated. Materials And Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic review (Moher et al. 2009). Search strategy PubMed, Embase, and Cochrane Library databases were searched for relevant studies from their inception to July 2019. The search was performed with a combination of Medical Subject Headings and free words as follows: (neoplasia OR neoplasm OR tumor OR cancer OR malignancy OR malignant neoplasm), and [disulfiram OR bis (diethylthiocarbamoyl) disulfide OR tetraethylthioperoxydicarbonic diamide OR tetraethylthiuram disulfide OR tetraethylthiuram OR antabus OR antabuse teturam OR dicupral OR esperal OR alcophobin OR anticol]. The details of the search strategy are presented in the supplement. Study selection Studies that implemented the below criteria were included: (1) cancer cell lines, animals, or patients treated with DSF; (2) in vitro studies focusing on parameters of the apoptosis index (early apoptosis or early apoptosis plus late apoptosis) using annexin V-fluorescein isothiocyanate/propidium iodide double-staining analysis by flow cytometry, in vivo studies evaluating the tumor inhibition rate in cell-line-derived xenograft animal models, or studies in humans, which included OS and PFS as endpoints, to assess the effect of DSF in cancer patients; and (3) studies published in the English and Chinese language. There were no restrictions on the type of cancer studied. To avoid duplication of data, only the most recent and most comprehensive articles were included. Studies with incomplete data or conference abstracts were excluded. Two investigators (Ling Wang, Run Wan) independently screened the databases for studies based on the eligibility criteria. Any discrepancies were resolved by consulting a third researcher (Cong Zhou). Data derivation Two investigators (Ling Wang, Cong Zhou) independently extracted data from the inclusive studies. Inconsistencies between the two investigators were resolved by consulting a third reviewer (Run Wan). When required, we contacted the authors of the research for further information. A pre-designed structured outline was used to abstract data. The outline included the following fields: study type (in vitro, in vivo, clinical study, or case series); general information (first author, publication year, country, and study design); supplement used; anticancer treatment used; and outcomes (i.e., apoptosis rate, tumor inhibition rate, OS and PFS, as applicable). The results of each study included were summarized. Descriptive statistics were used for data analysis. Meta-analysis was not performed owing to substantial heterogeneity across studies. Results Study characteristics The initial search yielded a total of 1278 studies. After excluding 274 irrelevant and duplicate studies, the full texts of 1004 studies were screened. Of these, 148 were considered eligible based on the availability of full texts as well as the description of target outcomes. Ultimately, 113 articles were removed (no full texts, n=43; no target outcomes, n=70), and 35 studies were selected. A detailed description of the steps followed during the retrieval process is provided in Figure 1. Of 35 selected studies, 21 were in vitro studies (Table 1), 11 were in vivo studies with animal models (Table 2), and three were clinical trials (Table 3). In in vitro studies, the most studied cancer was breast cancer (five studies) (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014), while the A549 non-small cell lung cancer (NSCLC) cell line was the one most commonly used cell line (four studies) (Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017). Three studies (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014) examined DSF as a single agent, and 17 studies (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017; Guo et al. 2019; Albers et al. 2018; Yang et al. 2017; AbuSerie et al. 2017; Zhao et al. 2015; Zhang et al. 2015; Han et al. 2013; Cen et al. 2002) examined DSF in combination with metal ions (Cu, Ag), chemotherapy, or radiation therapy. In addition, in three studies, DSF was encapsulated in nanoparticles (DSF-NPs) (Duan et al. 2014; Wang et al. 2017; Zhang et al. 2015). Table 1 Effects of disulfiram on cell apoptosis rates from in vitro studies Reference Country Tumor Percentage of apoptosis (%) Intervention time Negative control Posivitive control Cell lines Negative control Positive control Treatment group You et al (42) China Colorectal cancer 48hous Saline DOX (8.5 μM) HCT116 0.27 ± 0.24 29.2 ± 4.1 DSF/Cu 0.05 μM: 8.55 ± 2.3, 0.1 μM: 24.02 ± 3.6, 0.2 μM: 38.4 ± 7.9, 0.4 μM: 58.3 ± 7.7 HCT8 2.1±1.6 32.3 ± 4.1 DSF/Cu 0.05 μM: 29.5 ± 4.4, 0.1 μM: 28.1 ± 9.5, 0.2 μM: 38.6 ± 10.3, 0.4 μM: 56.4 ± 10.2 SW620 2.21±0.5 48.4 ± 9.5 DSF/Cu 0.05 μM: 20.1±5.7, 0.1 μM: 30 ± 4.2, 0.2 μM: 42 ± 6.3, 0.4 μM: 43.45 ± 8.3 Yang et al (8) Germany Breast cancer 48hours Control CIS (5 μM) MCF-7 25.31 31.67 DSF 1 μM: 36.6, DSF 1 μM + CIS 5 μM: 57.4 MDA-MB-435S 5.843 5.447 DSF 1 μM: 13.56, DSF 1 μM + CIS 5 μM: 29.4 SKB-R3 3.023 11.46 DSF 1 μM: 5.6, DSF 1 μM + CIS 5 μM: 7.71 Wu et al (9) China Triple-negative breast cancer 24hours DMSO PAX (5 nM) SUM102 ALDH+ 2.22 5.83 DSF/Cu 0.75 μM: 23.53 SUM102 ALDH- 8.01 10.81 DSF/Cu 0.75 μM: 20.9 Guo et al (20) Germany Ovarian cancer 72hours Control _ IGROV1 10.32 _ Cu 1 μM: 15.3, DSF 1 μM: 25.46, DSF/Cu: 47.55 SKOV3IP1 8.69 Cu 1 μM: 7.1, DSF 0.1 μM: 15.99, DSF/Cu: 55 SKOV3 3.65 Cu 1 μM: 1.91, DSF 1 μM: 43.2, DSF/Cu: 50.4 Wu et al (13) China Non-small cell lung cancer 24hours Control _ A549 2.5 _ Cu 1 μM: 3.8, DSF 1.4 μM: 4.8, DSF/Cu: 35.4 H460 4.7 Cu 1 μM: 3.7, DSF 8 μM: 4.9, DSF/Cu: 21.4 H1299 8.7 Cu 1 μM: 10.3, DSF 4 μM: 7.1, DSF/Cu: 37.9 Chen et al (14) China Non-small cell lung cancer 24hours Control _ A549 3.35 _ Ag 1.25 μM: 4.34, DSF 1.25 μM: 5.14, DSF/Ag: 42.81 Butcher et al (15) UK Non-small cell lung cancer 16hours Vehicle _ A549 6.3 _ CuCl 2 10 μM: 6.5, DSF 1 μM: 15.2, DSF/CuCL 2 : 47.2 Albers et al (21) Germany Head and neck squamous 48hours Control CIS(1μM)+10Gy HNSCC cell lines 11.35 CIS 1 μM: 24.12, 10Gy: 23.47 DSF 3 μM/Cu 0.1 μM: 20.87, DSF 3 μM + CIS 1 μM: 38.35, DSF 3 μM/Cu 0.1 μM + CIS 1 μM: 51 cell carcinoma CIS 1 μM + 10Gy: 30.68 DSF 3 μM: 17.66, CIS 1 μM + 10Gy+ DSF 3 μM: 44.82, CIS 1 μM + 10Gy+ DSF 3 μM/Cu 0.1 μM: 61.5 Yang et al (22) China Nasopharyngeal cancer 6hours Control _ CNE-2Z 4.41 _ DSF 0.2 μM/Cu 10 μM: 24.08, DSF 0.4 μM/Cu 10 μM: 58.2 NP69-SV40T 0.55 _ DSF 0.2 μM/Cu 10 μM: 1.19, DSF 0.4 μM/Cu 10 μM: 5.99 Marwa et al (23) Egypt Colon Cancer 72hours Control _ DCECs 1.58 _ DSF 9.5 ± 0.9 μg/mL: 60.31 ± 1.2, UC-NPs 1548.7 ± 25 μg/mL: 12.12 ± 0.47, C-NPs 3122.4 ± 39 μg/mL: 2.6 ± 0.07 CDCECs 0.28 _ DSF 23.9 ± 0.1 μg/mL: 57.78 ± 0.34, UC-NPs 77.7 ± 1.4 μg/mL: 54.75 ± 1.24, C-NPs 93.8 ± 0.4 μg/mL: 47.5 ± 0.31 Caco-2 0.05 _ DSF 39.6 ± 0.3 μg/mL: 53.62 ± 0.53, UC-NPs 97.9 ± 0.5 μg/mL: 53.49 ± 0.59, C-NPs 148.3 ± 0.1 μg/mL: 40.28 ± 0.24 Wang et al (16) China Non-small cell lung cancer 24hours Control _ A549 0.45 _ DSF-LP-PLGA-MP 1, 3, 5, 7days: 9.32, 27.1, 28.2, 49.18 Yang et al (10) China Breast cancer 24hours Control _ MCF-7 0.29 _ DSF 0.2 μM/CuCl 2 10 μM: 27.56, DSF 0.25μM/CuCl 2 10 μM: 86.8 Kim et al (11) Korea HER2-positive breast cancer 24hours DMSO _ SKBR3 3.16 _ Cu 1 μM: 2.91, DSF 1 μM: 2.6, DSF/Cu: 30.21 BT474 2.49 _ Cu 1 μM: 2.88, DSF 1 μM: 8, DSF/Cu: 40.76 Sharma et al (17) India Prostatic cancer 48hours Control STA (3mM) PC3 8.34±2.2 26.31±5.5 DSF 1 μM: 15.04±3.14, DSF 2 μM: 19.71±4.2, DSF 3 μM: 32.06±6.16 DU145 13.67±2.66 41.31±4.47 DSF 1 μM: 10.89±1.56, DSF 2 μM: 42.81±4.56, DSF 3 μM: 47.23±4.85 Zhao et al (24) China Pituitary adenomas 24hours Control TMZ (100μM) Pituitary adenoma cells 0.29±0.09 0.81±0.23 DSF 25 μM: 0.31±0.10, DSF 25 μM + TMZ 100 μM: 1.64±0.16 Zhang et al (25) China Hepatocellular carcinoma 24hours Control _ Hep G2 cells 1.3 _ DSF-S-LNCs (PH=7.4) : 9.4, DSF-S-LNCs (PH=6.5) : 16.5 Duan et al (12) China Breast cancer 24hours Control _ 4T1 1.07 _ DSF 1 μg: 34.77, DnMs (DSF 1 μg): 34.37, DCM (DSF 1 μg): 41.11 Rezk et al (18) USA Ovarian cancer 72hours Control _ A2780DK 4.15 _ DSF 5 μM: 36.4 Dastjerdi et al (19) Iran Pancreatic cancer 24hours Control _ PANC-1 27 _ DSF 5 μM: 51, DSF 10 μM: 84, DSF 13 μM: 92 Han et al (26) China Pancreatic cancer 72hours Control _ SW1990 1.5 _ DDTC–Cu(I) 1 μM: 6.4, DDTC–Cu(I) 3 μM: 17.7, DDTC–Cu(I) 5 μM: 24.8 Cen et al (27) USA Melanoma 48hours Control BSO (100M) C81-46A 12.057±0.72 13.194±1.11 DSF 50 ng/ml: 25.35 ± 1.21, DSF 50 ng/ml + BSO 100 M: 54.78 ± 2.83 Abbreviations: DOX, doxorubicin; CIS, cisplatin; PTX, paclitacel; STA, staurosporine; TMZ, temozolomide; BSO, buthionine-sulfoximine; DnMs: DSF loaded noncrosslinked micelles; DCM, DSF loaded redoxsensitive shell crosslinked micelle; DSF-LP-PLGA-MP, Disulfiram-loaded porous PLGA microparticle; UC-NPs, uncoated NPs; C-NPs, coated NPs; DDTC–Cu(I), diethyldithiocarbamate-Cu(I). Table 2 Effects of disulfiram on tumor inhibition rate from animal studies Information of reference Information of animals Intervention and tumor inhibition rate Toxicity evaluation Reference Country Tumor Strain and gender Old (weeks) Weight (g) Animal tumor model Interveniton methods Negative control Positive control Treatment group Inhibit Rate Parameter Outcome Peng et al(28) China Lung cancer Female Balb/C nude mice 4−5 18−22 1.0 × 10 6 A549 cells, SC, right flank every 4 days with 4 times, iv Saline _ DSF 10 mg/kg + copper 1.5 mg/kg ig PNpL-DSF/Cu(II)/DDC (1:1, 1mg/kg) TSR% =16.6% TSR% =51.6% No significant weight loss Low Parikshit et al (29) China Breast cancer Female Balb/C nude mice 4−5 18 ± 2 1.0 × 10 5 4T1 cells, SC, left armpit every 3 days with 6 times, iv Saline _ DSF 15 mg/kg DSF-NLC 15 mg/kg TPGS-DSF-NLC 15 mg/kg TGI%=8.49%. TGI%=29.2% TGI%=48.24% No noticeable body weight loss Safety Ji et al (30) China Breast cancer Female Balb/C nude mice _ 20 ± 2 8.0 × 10 5 4T1 cells, SC, right flank every days with 2weeks, iv or every day with 2weeks, ig Saline PTX (8mg/kg ) TSR%=55.01% DSF 20 mg/kg ig DSF-NSps 20 mg/kg ig DSF-NSps 20 mg/kg iv DSF-NSps 10 mg/kg iv DSF-NSps 5 mg/kg, iv TSR%=0% TSR%=59.03% TSR%=80% TSR%=75.86% TSR%=69.21% Weight increased slightly _ Zhou et al (37) China Liver cancer KunMing mice 5–6 _ 1.5 × 10 7 H-22 cells, SC, left axilla every 3 days with 4 times, iv Saline 5-FU (20 mg/kg ) TIR% =47.4% DSF NPs 3 mg/mL DSF NPs 40 mg/kg + Cu(OI)2-S 0.3 mg/kg DSF NPs 40 mg/kg + Cu(OI)2-L 0.3 mg/kg TIR% =26.8% TIR% =35.5% TIR% =50.3% _ _ Tao et al (31) China Breast cancer Female Balb/C nude mice _ 20 ± 2 3.0 × 10 6 4T1 cells, SC, right flank every 2 days with 4 times, iv Saline DOX (5 mg/kg ) TIR% =68.27% DSF 5 mg/kg DOX 5 mg/kg +DSF 5 mg/kg Co-NPs (DOX 5 mg/kg + DSF 5 mg/kg) TIR% =34.81% TIR% =80.92% TIR% =89.27% No significant difference in body weight change Safety Song et al (32) China Lung cancer Female Balb/C nude mice 6 20.0 2.0 × 10 6 A549DDP cells, SC, right flank every 2 days with 4 times, iv Saline _ PGA-CisPt 5.0 mg/kg PGA-CisPt 5.0 mg/kg+ NPs-DSF 10.mg/kg TSR%=45.6% TSR%=75.4% No body weight changes Safety Hamidreza et al (33) Iran Breast cancer Female Balb/C nude mice 5 _ 1.0 × 10 6 4T1 cells, mammary fat pad 2 weeks, iv Blank NPs _ DFS 10 mg/kg DS-P-NPs 10 mg/kg DS-PPF-NPs 10 mg/kg TSR%=17.07% TSR%=66.67% TSR%=75% DS-P-NPs, DS-PPF-NPs groups more reduction weight than the DSF No sign Song et al (34) China Breast cancer Balb/C mice 5-6 _ 2.0 × 10 6 4T1 cells, SC, right flank every 2 days with 6 times, iv Saline _ DSF 15 mg/kg NP4/5/1 15 mg/kg TSR%=0 TSR%=43.2% No obvious body weight loss Safety Jennifer et al (38) USA Breast tumor Female SCID mice _ _ 1.0 × 10 6 SUM149 cells, SC, flank daily, iv Vehicle _ DSF 50 mg/kg DSF 50 mg/kg + Cu 0.5 mg/kg TIR% =75% TIR% =84% No noticeable body weight change _ Choi et al (35) Korea Atypical teratoid/rhabdoid tumors Female Balb/C nude mice 7 _ 1.0 ×10 4 AT/RT cells, SC, _ every 5 consecutive days with 3weeks, ip DMSO _ DSF 100 mg/kg TSR%=72.25% _ No major Vino et al (36) China Malignant Pleural Mesothelioma Female Balb/C nude mice 5 _ 0.5 × 10 6 AB12 cells, SC, right flanks daily with 17 days, ip Vehicle _ DSF/Cu 50 mg/kg TSR%=71.5% Weight of DSF-Cu group was 75% lower than that of vehicle group _ Abbreviations: DOX, doxorubicin; Cis, cisplatin; 5-Fu, 5-fluorouracil; V, Volum; L, Length=longest diameter of the tumor; W, Width=shortest diameter of the tumor; SC, subcutaneous; iv, intravenous injection;TGI, tumor growth inhibition rate; TGI%= [(Vc1-Vt1)/(Vc0-Vt0)]×100%; TIR, tumor inhibition rate; TIR% = [(Vc-Vx)/Vc] ×100%; TSR, tumor suppression rate ; TSR% = [(Vc-Vx)/Vc] ×100%; Vc, mean tumor volume of the negative control group; Vt, mean tumor volume of certain administration group; Vc1, mean tumor volume in the negative control group at the time of tumor extraction; Vt1, mean tumor volume in the treatment groups at the time of tumor extraction; Vc0, mean tumor volumes in the negative control group; Vt 0, mean tumor volumes in the treatment group; NPs, nanoparticles; NSps, nanosuspensions; NLC, nanostructured lipid carriers; TPGS, D-alpha-Tocopheryl polyethylene glycol succinate; PNpL-DSF/Cu, Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate (DSF/Cu 1:1) ;Cu(OI)2-S: Administration of copper oleate solution; Cu(OI)2-L: Administration of copper oleate liposome; NP4/5/1, the feed ratio of mPEG-PLGA/PCL/DSF was 4/5/1 in mass; PLGA, Poly (lactide-co-glycolide) ; PEG, Poly(ethyleneglycol); mPEG-PLGA,methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide); PCL, polycaprolactone; DCC, N,N′ -Dicyclohexylcarbodiimide; DCM, Dichloromethane NHS, sulfo-N-hydroxysuccinimide; DS-PPF-NPs, disulfiram encapsulated PLGA PEG-folate NPs; DS-P-NPs, disulfiram encapsulated PLGA NPs. Of 11 animal studies, Balb/C nude mice were utilized in nine (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018), whereas the remaining studies used KunMing (Zhou et al. 2018) or female SCID (Allensworth et al. 2018) mice. Ten studies used subcutaneous tumor models by injecting cancer cell lines (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), and one study used an in situ tumor model (Fasehee et al. 2016). Eleven studies had assessed the dimensions of tumor volume (V) using the same formula (V= 0.5 × length × width 2 ) (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), nine studies assessed changes in body weight in mice (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), and six studies contained data regarding the toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015). In addition, eight of the animal studies used DSF by re-synthesizing the molecule with nanomaterials ((Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Zhou et al. 2018). The three human studies included participants with differing characteristics and cancer types. All three clinical trials investigated DSF as a combination therapy with chemotherapy or/and radiation therapy (Huang et al. 2019; Huang et al. 2018; You et al. 2019), while two studies reported on adverse events (Huang et al. 2019; Huang et al. 2018). Table 3 Eeffects of disulfiram on PFS and OS from human studies Reference Country Study design Study participants Study protocol OS PFS Adverse events Huang, et al (39) USA Phase II, open-label, single-arm study Recurrent GBM who had developed unequivocal progression after RT and concurrent TMZ as per "the RANO criteria while receiving adjuvant TMZ or within 3 months from the last dose of TMZ” DSF 80 mg and Cu Gluconate1.5 mg TID by mouth approximately 4–8h apart. 7.1 months (95% CI: 5.8–8.5) 1.7 months (95% CI: 1.4–1.9) Nausea/vomiting (17%) followed by dizziness (9% grade ),Only one patient (4%) had a possible DLT with grade three elevated alanine transaminase on day 31, which required study therapy to be held. The liver function test subsequently recovered after 4 weeks. Huang, et al (40) USA Phase I, open-label, single-arm, single-institution study Adjuvant TMZ in newly diagnosed adult GBM patients after standard chemoradiotherapy 7 patients at DSF 500 mg per day 5 patients at DSF 1000 mg per day, 6 patients at DSF 500 mg per day with Cu 2 mg 14.0 months (95% CI 8.3–19.6) 4.5 months (95% CI 0.8–8.2) one with delirium after 1.6 months (without Cu),one with motor neuropathy after 2.6 months (without Cu),one with diarrhea and nausea after 0.5 months (with Cu),All symptoms resolved shortly after dose reduction. Nechushtan, et al (41) Israel phase II, multicenter randomized double-blinded study Newly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time “wet IIIb” (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation. controls: six cycles of cisplatin and vinorelbine (plus placebo tablets), experimental groups: the same plus disulfiram (40mg three times daily). 10.0 versus 7.1 months 5.9 versus 4.9 months _ Abbreviations: GBM, glioblastoma; NSCLC, non-small cell lung cancer; TMZ, temozolomide; TID, three times per day; DLT, dose-limiting toxicity; RANO, Radiologic Assessment in Neuro-Oncology. Outcomes Three cell lines and one animal study showed that treatment with DSF as a single agent induced apoptosis and increased the rate of tumor inhibition (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014; Choi et al. 2015). Although the sensitivity between the various cell lines varied, dose-dependency was consistently observed. The concentration-dependent increase in apoptosis and tumor inhibition rates was augmented by a combination therapy of DSF adding metal ions [copper (Cu), silver (Ag)] in 10 in vitro (Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Guo et al. 2019; Yang et al. 2017; Han et al. 2013; Nechushtan et al. 2015) and three in vivo studies (Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015). The synergistic effect of Cis, DOX, TMZ, PTX, Gy, and DSF in induced apoptosis was significantly higher than that of DSF or Cis or DOX or TMZ or Gy alone (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Albers et al. 2014; Zhao et al. 2015; Nechushtan et al. 2015) Tumor cell growth was significantly inhibited when DSF, chemotherapy, and radiation therapy were used simultaneously, as shown in the examined in vivo studies (Ji et al. 2019; Tao et al. 2018;. Choi et al. 2015; Zhou et al. 2018). Compared with free molecule, DSF encapsulated with nanomaterials significantly induced selective death-dependent apoptosis, especially in acidic conditions (pH = 6.5) in cancer cell lines. Eleven animal studies demonstrated that DSF modified by particular nanomaterials increased the tumor inhibition rate and that the anticancer activity was more obvious when chemotherapy (Cis) was combined with nanoencapsulated DSF (Song et al. 2016). Changes in body weight during the whole study period were analyzed in nine animal studies. With the exception of three reports of weight changes in DSF-treated or DSF-modified groups (Ji et al. 2019; Fasehee et al. 2016; Cheriyan et al. 2018), other studies recorded that there was no noticeable body weight loss after DSF treatment or no significant difference in body weight changes across different groups (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), which indicated that there was no major toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015). Many clinical trials have mentioned the use of DSF for solid tumors (www.clinicaltrials.gov). One study clearly analyzed the difference in PFS (5.9 versus 4.9 months) and OS (10.0 versus 7.1 months) between control and experimental groups (Nechushtan et al. 2015). PFS and OS both improved in the experimental groups. Two studies described PFS and OS of the entire research cohort, and the treatment efficacy seemed to be in contrast to historical data (Huang et al. 2019; Huang et al. 2018). Our systemic review included two single-arm trials in glioblastoma (GBM) patients and a randomized controlled trial in NSCLC patients. Although the two single-arm clinical trials did not compare treatment with a control group, positive effects were observed; e.g., a 40-year-old woman with unmethylated isocitrate dehydrogenase wild-type GBM had good health without any signs of tumor recurrence 33 months after study initiation. Among the reported adverse effects, none were serious, and they were of Grade 2-3. Adverse effects were reported in two studies and included diarrhea, nausea, dizziness, vomiting, motor neuropathy, and elevated alanine transaminase levels. Symptoms resolved quickly when the dose was reduced (Huang et al. 2019; Huang et al. 2018). All three studies show that DSF is safe and seems to prolong survival of cancer patients. Because of individual differences in patients, the response to DSF was also varied (Huang et al. 2019; Huang et al. 2018; Nechushtan et al. 2015) .The optimal concentration and sensitivity type should be further explored by in vitro and animal studies. Discussion DSF is decomposed into diethyldithiocarbamate in the body and exhibits anticancer activities (Ekinci et al. 2013). Considering that the loss of cellular proliferation control leads to the development of cancer, effective clinical therapies of cancer have been developed based on the principle of inducing apoptosis (D'Arcy et al. 2019). In the included animal studies, the tumor inhibition rate was utilized to evaluate antitumor efficiency by calculating tumor volume. Most studies included in this review revealed enhanced apoptosis and tumor inhibition rates with DSF treatment. In recent years, metal-based complexes have been reported to exhibit anticancer activity (Schmitt et al. 2017). Silver complexes demonstrate anti-tumor activity and display low toxicity in humans. The mechanism of action is related to their interaction with nucleic acids and proteins (Banti et al. 2013). Metabolites of DSF chelate with metal ions, leading to alterations in the intracellular levels of metal ions, enhancement of oxidative stress, inhibition of the activities of superoxide dismutase or matrix metalloproteinases, inactivation of essential sulfhydryl groups by protein carbamoylation, and alteration of cancer cell invasion, tumor angiogenesis, and metastasis (Agarwa et al. 1986; Salem et al. 2015). The observation that the combination of DSF with metal ions (Cu, Ag) leads to enhanced anticancer effectiveness is in accordance with the observations of in vitro and animal experiments. The additive/synergistic action of DSF with other chemotherapy agents in inhibiting tumor cell growth and cytotoxicity is mediated through the enhancement of cellular oxidative stress, inhibition of P glycol-protein (P-gp) activity, and dysregulation of the NF-κB signaling pathway (Yang et al. 2019; Majera et al. 2019; Calderon et al. 2019). In the examined studies, anti-tumor activity, as evidenced by higher apoptosis and tumor inhibition rates, was enhanced with DSF-NPs in various ways. At the pH of 7.4, the half-life of DSF is 1-1.5 min (Agarwa et al. 1986). The half-life was improved by nanomaterial packaging of DSF, with the anti-tumor effects increasing under acidic conditions (pH = 6.5) (Miao et al. 2018). DSF-NPs enhanced cellular uptake, induced high levels of reactive oxygen species, activated the MAP-kinase pathway, sustained drug supply, and blocked copolymer micelles, such as the P-gp inhibitor (Guo et al. 2019; Huo et al. 2017; Chen et al. 2018). Evidence supports that DSF-NPs ameliorate the instability and low treatment efficacy of free DSF. Although our results may be more reliable than those of single studies, the present study has certain limitations. First, only articles published in English and Chinese were included; the non-inclusion of articles published in other languages may have had an effect on the results. Second, only four indicators were systematically evaluated, while others were not. Finally, no quality evaluation was conducted, and the majority of studies were animal and cell experiments; thus, the translation of these results to benefits in the clinic needs to be determined. In conclusion, this systematic review provides evidence of the antineoplastic activity of DSF in vitro , in in vivo animal models, and in humans. Many studies have investigated the antineoplastic activity of DSF, with most demonstrating its effectiveness and safety. However, caution is required when interpreting these results because the majority of evidence stems from in vivo or in vitro studies. Administration of DSF as a combination therapy or as a nanoparticle-encapsulated molecule seems to enhance its effectiveness, and these findings may serve as the basis for designing clinical studies of DSF in the future. Declarations Author contributions All authors read and approved the final version of this article. Ling Wang conceptualized the review, conducted the literature search, and was responsible for data extraction, data analysis, and for writing the original draft of this manuscript. Cong Zhou was responsible for data extraction. Run Wan conducted the literature search and served as an independent reviewer of the data extracted from the studies, responsible for solving any inconsistencies between Ling Wang and Cong Zhou. Yang Yu and Maswikiti Ewetse Paul contributed to the analysis and interpretation of study data. Yumin Li conceptualized the review, supervised the process, and was responsible for project administration and manuscript review. Funding This work was supported by grants from the National Natural Science Foundation of China (Grant No. 31770537) and the International Science and Technology Cooperation Project of Gansu Province (Grant No. 18YF1WA113). Disclosure statement Ling Wang, Yang Yu, Cong Zhou, Run Wan, Maswikiti Ewetse Paul, and Yumin Li declare that they have no conflicts of interest. References AbuSerie MM, El-Rashidy FH (2017) In Vitro Collapsing Colon Cancer Cells by Selectivity of Disulfiram-Loaded Charge Switchable Nanoparticles Against Cancer Stem Cells. Recent Pat Anticancer Drug Discov 12(3):260-271. Agarwal RP, Phillips M, McPherson RA et al (1986) Serum albumin and the metabolism of disulfiram Biochem Pharmacol 35(19):3341-3347. 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Huang J, Campian JL, Gujar AD et al (2018) Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma. J Neurooncol 138(1):105-111. Huang J, Chaudhary R, Cohen AL et al (2019) A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. J Neurooncol 142(3):537-544. Huo Q, Zhu J, Niu Y et al (2017) pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer. Int J Nanomedicine 128631-8647. Ji YB, Liu B, Yu RQ et al (2019) Preparation of disulfiram naonosuspensions and their anti-tumor efficacy in vitro and in vivo. Acta Pharmaceutica Sinica 54(3): 565 −573. Kaitin KI (2010) Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther 87(3):356-361. Kim JY, Cho Y, Oh E et al (2016) Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. Cancer Lett 379(1):39-48. Lewison EF (1977) Spontaneous regression of breast cancer. Prog Clin Biol Res 1247-53. Majera D, Skrott Z, Bouchal J et al (2019) Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram. Prostate 79(4):352-362. Miao L, Su J, Zhuo X et al (2018) mPEG5k- b-PLGA2k/PCL3.4k/MCT Mixed Micelles as Carriers of Disulfiram for Improving Plasma Stability and Antitumor Effect in Vivo. Mol Pharm 15(4):1556-1564. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006-1012. Nechushtan H, Hamamreh Y, Nidal S et al (2015) A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20(4):366-367. Peng X, Pan Q, Zhang B et al (2019) Highly Stable, Coordinated Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate for Combinational Chemo/Chemodynamic Therapy of Cancer. Biomacromolecules 20(6):2372-2383. Rezkk Y, Yang S, Bai K et al (2013) Disulfiram’s antineoplastic effects on ovarian cancer bulk tumor cells and the stem cell population: A study in ovarian cancer cell lines and in rodents. Gynecologic Oncology 130(1):e135-e136. Salem K, McCormick ML, Wendlandt E et al (2015) Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma. Redox Biol 423-33. Schmitt SM, Frezza M & Dou QP (2012) New applications of old metal-binding drugs in the treatment of human cancer. Front Biosci (Schol Ed) 4375-391. Sharma V, Verma V, Lal N et al (2016) Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor beta. Mol Carcinog 55(11):1843-1857. Song W, Tang Z, Lei T et al (2016a) Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy. Nanomedicine 12(2):377-386. Song W, Tang Z, Shen N et al (2016b) Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. Control Release 23194-102. Suh JJ, Pettinati HM, Kampman KM et al (2006) The status of disulfiram: a half of a century later. J Clin Psychopharmacol 26(3):290-302. Tao X, Gou J, Zhang Q et al (2018) Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles. Biomater Sci 6(7):1869-1881. Wang C, Yang J, Han H et al (2017) Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer. Int J Nanomedicine 12827-837. Wu L, Meng F, Dong L et al (2019) Disulfiram and BKM120 in Combination with Chemotherapy Impede Tumor Progression and Delay Tumor Recurrence in Tumor Initiating Cell-Rich TNBC. Sci Rep 9(1):236. Wu X, Xue X, Wang L et al (2018) Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. Eur J Pharmacol 8271-12. Yang Y, Li M, Sun X et al (2017) The selective cytotoxicity of DSF-Cu attributes to the biomechanical properties and cytoskeleton rearrangements in the normal and cancerous nasopharyngeal epithelial cells. Int J Biochem Cell Biol 8496-108. Yang Y, Zhang K, Wang Y et al (2016) Disulfiram chelated with copper promotes apoptosis in human breast cancer cells by impairing the mitochondria functions. Scanning 38(6):825-836. Yang Z, Guo F, Albers AE et al (2019) Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother 113108727. You SY, Rui W, Chen ST et al (2019) Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate. Biochem Biophys Res Commun 513(4):891-897. Zhang L, Tian B, Li Y et al (2015) A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding TAT Peptide-Modified Lipid Nanocapsules for Use in Tumor Therapy. ACS Appl Mater Interfaces 7(45):25147-25161. Zhao Y, Xiao Z, Chen W et al (2015) Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression. Mol Med Rep 12(2):2313-2322. Zhou L, Yang L, Yang C et al (2018) Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo. Pharm Res 35(7):147. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 26 Jul, 2021 Review # 2 received at journal 15 Jul, 2021 Review # 1 received at journal 03 Jul, 2021 Reviewer # 2 agreed at journal 02 Jul, 2021 Reviews received at journal 02 Jul, 2021 Reviewer # 1 agreed at journal 02 Jul, 2021 Reviewers invited by journal 21 Jun, 2021 Editor assigned by journal 07 Jun, 2021 Editor invited by journal 06 Jun, 2021 Submission checks completed at journal 03 Jan, 2021 First submitted to journal 29 Dec, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-140063","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Methodology","associatedPublications":[],"authors":[{"id":7417805,"identity":"e08cdbef-4617-4adb-ada8-df38dfd790a6","order_by":0,"name":"ling wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYBACxvkP0n//MKjhkWdvIFILc0PCA2mGimNyhj0HiNTC3pAI1HKG2ZjhRgKRWngbDicYF7axJTbOfLzxBkONTTRBLZKNbQnJM9tkEtul04otGI6l5TYQ0mLYzJNwgBdky+wcMwnGhsOEtdgf4//YwNvGnNhw8wyRWhh7GJKZecDe5yFWywyGNMYZ4EAG+iWBGL+AtDB8AEfl4Y03PtTYENaCDAwkEkhRDtFCqo5RMApGwSgYGQAAT8tBcBHFy74AAAAASUVORK5CYII=","orcid":"","institution":"First People's Hospital of Lanzhou City","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"ling","middleName":"","lastName":"wang","suffix":""},{"id":7417806,"identity":"59d5f426-a803-4eac-8315-5ca378a2171c","order_by":1,"name":"yang yu","email":"","orcid":"","institution":"lanzhou university","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"yang","middleName":"","lastName":"yu","suffix":""},{"id":7417807,"identity":"13871e44-5e04-423f-ab31-8f723611dec2","order_by":2,"name":"cong zhou","email":"","orcid":"","institution":"lanzhou university","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"cong","middleName":"","lastName":"zhou","suffix":""},{"id":7417808,"identity":"754138b0-1ce2-4578-b6f2-8a695fc75fa9","order_by":3,"name":"run wan","email":"","orcid":"","institution":"lanzhou university","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"run","middleName":"","lastName":"wan","suffix":""},{"id":7417809,"identity":"bedac545-8661-4012-aff0-7d093e848994","order_by":4,"name":"Yumin Li","email":"","orcid":"","institution":"lanzhou university","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yumin","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2021-01-03 22:36:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-140063/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-140063/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4999039,"identity":"a8639b10-019d-48ca-84a5-0fc3522fa8c2","added_by":"auto","created_at":"2021-01-15 17:03:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54809,"visible":true,"origin":"","legend":"Flow diagram of literature search process","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-140063/v1/e78f3901b38a0baefc35d3ac.png"},{"id":13646852,"identity":"82f589da-e315-478d-9b87-0b97d6105c3c","added_by":"auto","created_at":"2021-09-17 09:25:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":299555,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-140063/v1/e5618971-6464-43d2-8796-76859580522e.pdf"}],"financialInterests":"","formattedTitle":"Anticancer Effects of Disulfiram: A Systematic Review of in Vitro, Animal, and Human Studies","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer is expected to be the leading cause of death and the foremost contributor to decreased life expectancy in every country worldwide during the 21st century and beyond. Although comprehensive therapies prolong survival and improve the quality of life of cancer patients, approximately 96,000,000 cancer deaths occurred in 2018 (Bray et al. 2018). The global community is well aware that new drug development, discovery, and synthesis is a time-consuming process, which involves intensive work and appraisal of the cost-effectiveness of the drug under development (Kaitin et al. 2010). As a result, researchers are allocating considerable efforts for repurposing existing drugs such as disulfiram (DSF).\u003c/p\u003e\n\u003cp\u003eIn the 1800s, DSF was used as an industrial catalyst in the production of rubber (Suh et al. 2006). In 1948, DSF was approved by the Food and Drug Administration for treating alcoholism (Eneanya et al. 1981). In 1988, DSF was associated with a decrease in the occurrence of occasional infections in symptomatic patients with human immunodeficiency virus infection (Gotzsche et al. 1988), prompting the conduct of a wealth of clinical trials, some of which are still ongoing (\u003ca href=\"http://www.clinicaltrials.gov\"\u003ewww.clinicaltrials.gov\u003c/a\u003e). The antineoplastic activity of DSF was first recorded in 1977 by Dr. Lewison in a 35-year-old female breast cancer patient with systemic metastases who received DSF for her severe alcoholic syndrome and remained clinically free of cancer for 10 years without receiving any form of anticancer therapy (Lewison et al. 1977). This observation was noted in\u0026nbsp;an\u0026nbsp;era\u0026nbsp;in\u0026nbsp;which the anticancer effect of DSF was being researched. In recent years, a large number of preclinical studies and clinical trials (\u003ca href=\"http://www.clinicaltrials.gov\"\u003ewww.clinicaltrials.gov\u003c/a\u003e) of DSF have been conducted to explore the anticancer activities of this drug. Nonetheless, the antitumor effectiveness of DSF remains uncertain owing to existing heterogeneity across different studies with cell lines, animals, and humans. Currently, a systematic review of these studies to assess and clarify the anticancer potential of DSF is lacking.\u003c/p\u003e\n\u003cp\u003eIt is worthy to explore whether there are substantial differences and are appropriate for clinical proposals. Therefore, this study aimed to perform a systematic review of published data on the antitumor activity of DSF. Specifically, this review aimed to assess the apoptosis and tumor inhibition rates of DSF based on data from studies in cell lines and animal models, respectively, and examine the benefit of DSF on progression-free survival (PFS) and overall survival (OS) based on results from clinical studies, regardless of the study design or type of cancer investigated.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic review (Moher et al. 2009).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eSearch strategy\u003c/h2\u003e\n\u003cp\u003ePubMed, Embase, and Cochrane Library databases were searched for relevant studies from their inception to July 2019. The search was performed with a combination of Medical Subject Headings and free words as follows: (neoplasia OR neoplasm OR tumor OR cancer OR malignancy OR malignant neoplasm), and [disulfiram OR bis (diethylthiocarbamoyl) disulfide OR tetraethylthioperoxydicarbonic diamide OR tetraethylthiuram disulfide OR tetraethylthiuram OR antabus OR antabuse teturam OR dicupral OR esperal OR alcophobin OR anticol]. The details of the search strategy are presented in the supplement.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eStudy selection\u003c/h2\u003e\n\u003cp\u003eStudies that implemented the below criteria were included: (1) cancer cell lines, animals, or patients treated with DSF; (2) in vitro studies focusing on parameters of the apoptosis index (early apoptosis or early apoptosis plus late apoptosis) using annexin V-fluorescein isothiocyanate/propidium iodide double-staining analysis by flow cytometry, in vivo studies evaluating the tumor inhibition rate in cell-line-derived xenograft animal models, or studies in humans, which included OS and PFS as endpoints, to assess the effect of DSF in cancer patients; and (3) studies published in the English and Chinese language. There were no restrictions on the type of cancer studied. To avoid duplication of data, only the most recent and most comprehensive articles were included. Studies with incomplete data or conference abstracts were excluded. Two investigators (Ling Wang, Run Wan) independently screened the databases for studies based on the eligibility criteria. Any discrepancies were resolved by consulting a third researcher (Cong Zhou).\u003c/p\u003e\n\u003ch2\u003eData derivation\u003c/h2\u003e\n\u003cp\u003eTwo investigators (Ling Wang, Cong Zhou) independently extracted data from the inclusive studies. Inconsistencies between the two investigators were resolved by consulting a third reviewer (Run Wan). When required, we contacted the authors of the research for further information. A pre-designed structured outline was used to abstract data. The outline included the following fields: study type (in vitro, in vivo, clinical study, or case series); general information (first author, publication year, country, and study design); supplement used; anticancer treatment used; and outcomes (i.e., apoptosis rate, tumor inhibition rate, OS and PFS, as applicable). The results of each study included were summarized. Descriptive statistics were used for data analysis. Meta-analysis was not performed owing to substantial heterogeneity across studies.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eStudy characteristics\u003c/h2\u003e\n\u003cp\u003eThe initial search yielded a total of 1278 studies. After excluding 274 irrelevant and duplicate studies, the full texts of 1004 studies were screened. Of these, 148 were considered eligible based on the availability of full texts as well as the description of target outcomes. Ultimately, 113 articles were removed (no full texts, n=43; no target outcomes, n=70), and 35 studies were selected. A detailed description of the steps followed during the retrieval process is provided in Figure 1.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;Of 35 selected studies, 21 were in vitro studies (Table 1), 11 were in vivo studies with animal models (Table 2), and three were clinical trials (Table 3). In in vitro studies, the most studied cancer was breast cancer (five studies) (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014), while the A549 non-small cell lung cancer (NSCLC) cell line was the one most commonly used cell line (four studies) (Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017). Three studies (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014) examined DSF as a single agent, and 17 studies (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017; Guo et al. 2019; Albers et al. 2018; Yang et al. 2017; AbuSerie et al. 2017; Zhao et al. 2015; Zhang et al. 2015; Han et al. 2013; Cen et al. 2002) examined DSF in combination with metal ions (Cu, Ag), chemotherapy, or radiation therapy. In addition, in three studies, DSF was encapsulated in nanoparticles (DSF-NPs) (Duan et al. 2014; Wang et al. 2017; Zhang et al. 2015).\u0026nbsp;\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEffects of disulfiram on cell apoptosis rates from in vitro studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCountry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTumor\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" width=\"510\"\u003e\n\u003cp\u003ePercentage of apoptosis (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003eIntervention\u003c/p\u003e\n\u003cp\u003etime\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eNegative control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003ePosivitive control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eCell lines\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eNegative control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003ePositive control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eTreatment group\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eYou et al (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003eColorectal cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"57\"\u003e\n\u003cp\u003e48hous\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"65\"\u003e\n\u003cp\u003eDOX\u003c/p\u003e\n\u003cp\u003e(8.5 \u0026mu;M)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eHCT116\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.27 \u0026plusmn; 0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e29.2 \u0026plusmn; 4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF/Cu 0.05 \u0026mu;M: 8.55 \u0026plusmn; 2.3, 0.1 \u0026mu;M: 24.02 \u0026plusmn; 3.6, 0.2 \u0026mu;M: 38.4 \u0026plusmn; 7.9, 0.4 \u0026mu;M: 58.3 \u0026plusmn; 7.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eHCT8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e2.1\u0026plusmn;1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e32.3 \u0026plusmn; 4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF/Cu 0.05 \u0026mu;M: 29.5 \u0026plusmn; 4.4, 0.1 \u0026mu;M: 28.1 \u0026plusmn; 9.5, 0.2 \u0026mu;M: 38.6 \u0026plusmn; 10.3, 0.4 \u0026mu;M: 56.4 \u0026plusmn; 10.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSW620\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e2.21\u0026plusmn;0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e48.4 \u0026plusmn; 9.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF/Cu 0.05 \u0026mu;M: 20.1\u0026plusmn;5.7, 0.1 \u0026mu;M: 30 \u0026plusmn; 4.2, 0.2 \u0026mu;M: 42 \u0026plusmn; 6.3, 0.4 \u0026mu;M: 43.45 \u0026plusmn; 8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eYang et al (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eGermany\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"57\"\u003e\n\u003cp\u003e48hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"65\"\u003e\n\u003cp\u003eCIS\u003c/p\u003e\n\u003cp\u003e(5 \u0026mu;M)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eMCF-7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e25.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e31.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;M: 36.6, DSF 1 \u0026mu;M + CIS 5 \u0026mu;M: 57.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eMDA-MB-435S\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e5.843\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e5.447\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;M: 13.56, DSF 1 \u0026mu;M + CIS 5 \u0026mu;M: 29.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSKB-R3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e3.023\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e11.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;M: 5.6, DSF 1 \u0026mu;M + CIS 5 \u0026mu;M: 7.71\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eWu et al (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003eTriple-negative breast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eDMSO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"65\"\u003e\n\u003cp\u003ePAX\u003c/p\u003e\n\u003cp\u003e(5 nM)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSUM102 ALDH+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e2.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e5.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF/Cu 0.75 \u0026mu;M: 23.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSUM102 ALDH-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e8.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e10.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF/Cu 0.75 \u0026mu;M: 20.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eGuo et al (20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eGermany\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003eOvarian cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"57\"\u003e\n\u003cp\u003e72hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eIGROV1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e10.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 15.3, DSF 1 \u0026mu;M: 25.46, DSF/Cu: 47.55\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSKOV3IP1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e8.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 7.1, DSF 0.1 \u0026mu;M: 15.99, DSF/Cu: 55\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSKOV3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e3.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 1.91, DSF 1 \u0026mu;M: 43.2, DSF/Cu: 50.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eWu et al (13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eA549\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e2.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 3.8, DSF 1.4 \u0026mu;M: 4.8, DSF/Cu: 35.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eH460\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e4.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 3.7, DSF 8 \u0026mu;M: 4.9, DSF/Cu: 21.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eH1299\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e8.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 10.3, DSF 4 \u0026mu;M: 7.1, DSF/Cu: 37.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChen et al (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eA549\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e3.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eAg 1.25 \u0026mu;M: 4.34, DSF 1.25 \u0026mu;M: 5.14, DSF/Ag: 42.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eButcher et al (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eUK\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e16hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eVehicle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eA549\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e6.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCuCl\u003csub\u003e2\u003c/sub\u003e 10 \u0026mu;M: 6.5, DSF 1 \u0026mu;M: 15.2, DSF/CuCL\u003csub\u003e2\u003c/sub\u003e: 47.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eAlbers et al (21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eGermany\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eHead and neck squamous\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e48hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"65\"\u003e\n\u003cp\u003eCIS(1\u0026mu;M)+10Gy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003eHNSCC cell lines\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003e11.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003eCIS 1 \u0026mu;M: 24.12, 10Gy: 23.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 3 \u0026mu;M/Cu 0.1 \u0026mu;M: 20.87, DSF 3 \u0026mu;M + CIS 1 \u0026mu;M: 38.35,\u0026nbsp; DSF 3 \u0026mu;M/Cu 0.1 \u0026mu;M + CIS 1 \u0026mu;M: 51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ecell carcinoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003eCIS 1 \u0026mu;M + 10Gy: 30.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 3 \u0026mu;M: 17.66, CIS 1 \u0026mu;M + 10Gy+ DSF 3 \u0026mu;M: 44.82, CIS 1 \u0026mu;M + 10Gy+ DSF 3 \u0026mu;M/Cu 0.1 \u0026mu;M: 61.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eYang et al (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003eNasopharyngeal cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e6hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eCNE-2Z\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e4.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 0.2 \u0026mu;M/Cu 10 \u0026mu;M: 24.08, DSF 0.4 \u0026mu;M/Cu 10 \u0026mu;M: 58.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eNP69-SV40T\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 0.2 \u0026mu;M/Cu 10 \u0026mu;M: 1.19, DSF 0.4 \u0026mu;M/Cu 10 \u0026mu;M: 5.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eMarwa et al (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"76\"\u003e\n\u003cp\u003eColon Cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"57\"\u003e\n\u003cp\u003e72hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eDCECs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 9.5 \u0026plusmn; 0.9 \u0026mu;g/mL: 60.31 \u0026plusmn; 1.2, UC-NPs 1548.7 \u0026plusmn; 25 \u0026mu;g/mL: 12.12 \u0026plusmn; 0.47, C-NPs 3122.4 \u0026plusmn; 39 \u0026mu;g/mL: 2.6 \u0026plusmn; 0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eCDCECs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 23.9 \u0026plusmn; 0.1 \u0026mu;g/mL: 57.78 \u0026plusmn; 0.34, UC-NPs 77.7 \u0026plusmn; 1.4 \u0026mu;g/mL: 54.75 \u0026plusmn; 1.24, C-NPs 93.8 \u0026plusmn; 0.4 \u0026mu;g/mL: 47.5 \u0026plusmn; 0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eCaco-2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 39.6 \u0026plusmn; 0.3 \u0026mu;g/mL: 53.62 \u0026plusmn; 0.53, UC-NPs 97.9 \u0026plusmn; 0.5 \u0026mu;g/mL: 53.49 \u0026plusmn; 0.59, C-NPs 148.3 \u0026plusmn; 0.1 \u0026mu;g/mL: 40.28 \u0026plusmn; 0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eWang et al (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eA549\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF-LP-PLGA-MP 1, 3, 5, 7days: 9.32, 27.1, 28.2, 49.18\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eYang et al (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eMCF-7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 0.2 \u0026mu;M/CuCl\u003csub\u003e2\u003c/sub\u003e 10 \u0026mu;M: 27.56, DSF 0.25\u0026mu;M/CuCl\u003csub\u003e2\u003c/sub\u003e 10 \u0026mu;M: 86.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eKim et al (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eKorea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003eHER2-positive breast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eDMSO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSKBR3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e3.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 2.91, DSF 1 \u0026mu;M: 2.6, DSF/Cu: 30.21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eBT474\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e2.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eCu 1 \u0026mu;M: 2.88, DSF 1 \u0026mu;M: 8, DSF/Cu: 40.76\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eSharma et al (17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eIndia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"76\"\u003e\n\u003cp\u003eProstatic cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e48hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"65\"\u003e\n\u003cp\u003eSTA (3mM)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePC3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e8.34\u0026plusmn;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e26.31\u0026plusmn;5.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;M: 15.04\u0026plusmn;3.14, DSF 2 \u0026mu;M: 19.71\u0026plusmn;4.2, DSF 3 \u0026mu;M: 32.06\u0026plusmn;6.16\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eDU145\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e13.67\u0026plusmn;2.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e41.31\u0026plusmn;4.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;M: 10.89\u0026plusmn;1.56, DSF 2 \u0026mu;M: 42.81\u0026plusmn;4.56, DSF 3 \u0026mu;M: 47.23\u0026plusmn;4.85\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eZhao et al (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePituitary adenomas\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003eTMZ\u003c/p\u003e\n\u003cp\u003e(100\u0026mu;M)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePituitary adenoma cells\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.29\u0026plusmn;0.09\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e0.81\u0026plusmn;0.23\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 25 \u0026mu;M: 0.31\u0026plusmn;0.10,\u0026nbsp; DSF 25 \u0026mu;M + TMZ 100 \u0026mu;M: 1.64\u0026plusmn;0.16\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eZhang et al (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eHepatocellular carcinoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eHep G2 cells\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF-S-LNCs (PH=7.4) : 9.4, DSF-S-LNCs (PH=6.5) : 16.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eDuan et al (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e4T1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 1 \u0026mu;g: 34.77, \u0026nbsp;DnMs (DSF 1 \u0026mu;g): 34.37, \u0026nbsp;DCM (DSF 1 \u0026mu;g): 41.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eRezk et al (18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eUSA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eOvarian cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e72hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eA2780DK\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e4.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 5 \u0026mu;M: 36.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eDastjerdi et al (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePancreatic cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e24hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePANC-1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 5 \u0026mu;M: 51, DSF 10 \u0026mu;M: 84, DSF 13 \u0026mu;M: 92\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eHan et al (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePancreatic cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e72hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eSW1990\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDDTC\u0026ndash;Cu(I) 1 \u0026mu;M: 6.4, DDTC\u0026ndash;Cu(I) 3 \u0026mu;M: 17.7, DDTC\u0026ndash;Cu(I) 5 \u0026mu;M: 24.8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eCen et al (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eUSA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eMelanoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e48hours\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"47\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"65\"\u003e\n\u003cp\u003eBSO (100M)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eC81-46A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e12.057\u0026plusmn;0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"66\"\u003e\n\u003cp\u003e13.194\u0026plusmn;1.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"369\"\u003e\n\u003cp\u003eDSF 50 ng/ml: 25.35 \u0026plusmn; 1.21, DSF 50 ng/ml + BSO 100 M: 54.78 \u0026plusmn; 2.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\" width=\"47\"\u003e\n\u003cp\u003eAbbreviations: DOX, doxorubicin; CIS, cisplatin; PTX, paclitacel; STA, staurosporine; TMZ, temozolomide; BSO, buthionine-sulfoximine; DnMs: DSF loaded noncrosslinked micelles; DCM, DSF loaded redoxsensitive shell crosslinked micelle; DSF-LP-PLGA-MP, Disulfiram-loaded porous PLGA microparticle; UC-NPs, uncoated NPs; C-NPs, coated NPs; DDTC\u0026ndash;Cu(I), diethyldithiocarbamate-Cu(I).\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ctable id=\"Tab1\" style=\"margin-left: auto; margin-right: auto;\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEffects of disulfiram on tumor inhibition rate from animal studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" width=\"167\"\u003e\n\u003cp\u003eInformation of reference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" width=\"167\"\u003e\n\u003cp\u003eInformation of animals\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"266\"\u003e\n\u003cp\u003eIntervention and tumor inhibition rate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"107\"\u003e\n\u003cp\u003eToxicity evaluation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eCountry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eTumor\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eStrain and gender\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003eOld (weeks)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003eWeight (g)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eAnimal tumor model\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003eInterveniton\u003c/p\u003e\n\u003cp\u003emethods\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003eNegative control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003ePositive control\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eTreatment group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eInhibit Rate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003ePeng et al(28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eLung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e4\u0026minus;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e18\u0026minus;22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e1.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e A549 cells, SC, right flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003eevery 4 days with 4 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eDSF 10 mg/kg + copper 1.5 mg/kg ig PNpL-DSF/Cu(II)/DDC (1:1, 1mg/kg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eTSR% =16.6% TSR% =51.6%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003eNo significant weight loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eLow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"48\"\u003e\n\u003cp\u003eParikshit et al (29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e4\u0026minus;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e18 \u0026plusmn; 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e1.0 \u0026times; 10\u003csup\u003e5\u003c/sup\u003e 4T1 cells, SC, left armpit\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"56\"\u003e\n\u003cp\u003eevery 3 days with 6 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eDSF 15 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF-NLC 15 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; TPGS-DSF-NLC 15 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eTGI%=8.49%. TGI%=29.2% TGI%=48.24%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"61\"\u003e\n\u003cp\u003eNo noticeable body weight loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eSafety\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"5\" width=\"48\"\u003e\n\u003cp\u003eJi et al (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"77\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"38\"\u003e\n\u003cp\u003e20 \u0026plusmn; 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"46\"\u003e\n\u003cp\u003e8.0 \u0026times; 10\u003csup\u003e5\u003c/sup\u003e 4T1 cells, SC, right flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"56\"\u003e\n\u003cp\u003eevery days with 2weeks, iv\u0026nbsp; or every day with 2weeks, ig\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"49\"\u003e\n\u003cp\u003ePTX \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;(8mg/kg )\u003c/p\u003e\n\u003cp\u003eTSR%=55.01%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"77\"\u003e\n\u003cp\u003eDSF 20 mg/kg ig\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF-NSps 20 mg/kg ig\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF-NSps 20 mg/kg iv\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF-NSps 10 mg/kg iv\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF-NSps 5 mg/kg, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"43\"\u003e\n\u003cp\u003eTSR%=0% TSR%=59.03% TSR%=80% TSR%=75.86% TSR%=69.21%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"61\"\u003e\n\u003cp\u003eWeight increased slightly\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"5\" width=\"46\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"48\"\u003e\n\u003cp\u003eZhou et al (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eLiver cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eKunMing mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e5\u0026ndash;6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e1.5 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e H-22 cells, SC, left axilla\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"56\"\u003e\n\u003cp\u003eevery 3 days with 4 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"49\"\u003e\n\u003cp\u003e5-FU\u003c/p\u003e\n\u003cp\u003e(20 mg/kg )\u003c/p\u003e\n\u003cp\u003eTIR% =47.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eDSF NPs 3 mg/mL\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF NPs 40 mg/kg + Cu(OI)2-S 0.3 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DSF NPs 40 mg/kg + Cu(OI)2-L 0.3 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eTIR% =26.8%\u0026nbsp; TIR% =35.5% TIR% =50.3%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"61\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"48\"\u003e\n\u003cp\u003eTao et al (31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e20 \u0026plusmn; 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e3.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e 4T1 cells, SC, right flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"56\"\u003e\n\u003cp\u003eevery 2 days with 4 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"49\"\u003e\n\u003cp\u003eDOX\u003c/p\u003e\n\u003cp\u003e(5 mg/kg )\u003c/p\u003e\n\u003cp\u003eTIR% =68.27%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eDSF 5 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DOX 5 mg/kg +DSF 5 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Co-NPs (DOX 5 mg/kg + DSF 5 mg/kg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eTIR% =34.81%\u0026nbsp; TIR% =80.92% TIR% =89.27%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"61\"\u003e\n\u003cp\u003eNo significant difference in body weight change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eSafety\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003eSong et al (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLung cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e20.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e2.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e A549DDP cells, SC, right flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003eevery 2 days with 4 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003ePGA-CisPt 5.0 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; PGA-CisPt 5.0 mg/kg+ NPs-DSF 10.mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eTSR%=45.6% TSR%=75.4%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003eNo body weight changes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSafety\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"48\"\u003e\n\u003cp\u003eHamidreza et al (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e1.0\u0026nbsp; \u0026times; 10\u003csup\u003e6 \u003c/sup\u003e\u0026nbsp;4T1 cells, mammary fat pad\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"56\"\u003e\n\u003cp\u003e2 weeks, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"42\"\u003e\n\u003cp\u003eBlank NPs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eDFS 10 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;DS-P-NPs 10 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; DS-PPF-NPs 10 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eTSR%=17.07% TSR%=66.67% TSR%=75%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"61\"\u003e\n\u003cp\u003eDS-P-NPs, DS-PPF-NPs groups more reduction weight than the DSF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eNo sign\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003eSong et al (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eBreast cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eBalb/C mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e5-6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e2.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e 4T1 cells, SC, right flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003eevery 2 days with 6 times, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003eSaline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eDSF 15 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;NP4/5/1 15 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eTSR%=0\u003c/p\u003e\n\u003cp\u003eTSR%=43.2%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003eNo obvious body weight loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eSafety\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003eJennifer et al (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eUSA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eBreast tumor\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eSCID mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e1.0 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e SUM149 cells, SC, flank\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003edaily, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003eVehicle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eDSF 50 mg/kg\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;DSF 50 mg/kg + Cu 0.5 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eTIR% =75%\u0026nbsp; TIR% =84%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003eNo noticeable body weight change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"48\"\u003e\n\u003cp\u003eChoi et al (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eKorea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eAtypical teratoid/rhabdoid tumors\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003e1.0 \u0026times;10\u003csup\u003e4\u003c/sup\u003e AT/RT cells, SC, _\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"56\"\u003e\n\u003cp\u003eevery 5\u003c/p\u003e\n\u003cp\u003econsecutive days with 3weeks, ip\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"42\"\u003e\n\u003cp\u003eDMSO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"77\"\u003e\n\u003cp\u003eDSF 100 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"43\"\u003e\n\u003cp\u003eTSR%=72.25%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"61\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"46\"\u003e\n\u003cp\u003eNo major\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"48\"\u003e\n\u003cp\u003eVino et al (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eChina\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eMalignant Pleural Mesothelioma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eBalb/C nude mice\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"38\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e0.5 \u0026times; 10\u003csup\u003e6\u0026nbsp; \u003c/sup\u003eAB12 cells, SC, right flanks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"56\"\u003e\n\u003cp\u003edaily with 17 days, ip\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"42\"\u003e\n\u003cp\u003eVehicle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"49\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"77\"\u003e\n\u003cp\u003eDSF/Cu 50 mg/kg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"43\"\u003e\n\u003cp\u003eTSR%=71.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"61\"\u003e\n\u003cp\u003eWeight of DSF-Cu group was 75% lower than that of vehicle group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"46\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"0\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DOX, doxorubicin; Cis, cisplatin; 5-Fu, 5-fluorouracil; V, Volum; L, Length=longest diameter of the tumor; W, Width=shortest diameter of the tumor; SC, subcutaneous; iv, intravenous injection;TGI, tumor growth inhibition rate; TGI%= [(Vc1-Vt1)/(Vc0-Vt0)]\u0026times;100%; TIR, tumor inhibition rate; TIR% = [(Vc-Vx)/Vc] \u0026times;100%; TSR, tumor suppression rate ; TSR% = [(Vc-Vx)/Vc] \u0026times;100%; Vc, mean tumor volume of the negative control group; Vt, mean tumor volume of certain administration group; Vc1, mean tumor volume in the negative control group at the time of tumor extraction; Vt1, mean tumor volume in the treatment groups at the time of tumor extraction; Vc0, mean tumor volumes in the negative control group; Vt 0, mean tumor volumes in the treatment group; NPs, nanoparticles; NSps, nanosuspensions; NLC, nanostructured lipid carriers; TPGS, D-alpha-Tocopheryl polyethylene glycol succinate; PNpL-DSF/Cu, Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate (DSF/Cu 1:1) ;Cu(OI)2-S: Administration of copper oleate solution; Cu(OI)2-L: Administration of copper oleate liposome; NP4/5/1, the feed ratio of mPEG-PLGA/PCL/DSF was 4/5/1 in mass;\u0026nbsp; PLGA, Poly (lactide-co-glycolide) ; PEG, Poly(ethyleneglycol); mPEG-PLGA,methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide); PCL, polycaprolactone; DCC, N,N\u0026prime; -Dicyclohexylcarbodiimide; DCM, Dichloromethane NHS, sulfo-N-hydroxysuccinimide; DS-PPF-NPs, disulfiram encapsulated PLGA PEG-folate NPs; DS-P-NPs, disulfiram encapsulated PLGA NPs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf 11 animal studies, Balb/C nude mice were utilized in nine (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018), whereas the remaining studies used KunMing (Zhou et al. 2018) or female SCID (Allensworth et al. 2018) mice. Ten studies used subcutaneous tumor models by injecting cancer cell lines (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), and one study used an in situ tumor model (Fasehee et al. 2016). Eleven studies had assessed the dimensions of tumor volume (V) using the same formula (V= 0.5 \u0026times; length \u0026times; width\u003csup\u003e2\u003c/sup\u003e) (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), nine studies assessed changes in body weight in mice (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), and six studies contained data regarding the toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015). In addition, eight of the animal studies used DSF by re-synthesizing the molecule with nanomaterials ((Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Zhou et al. 2018).\u003c/p\u003e\n\u003cp\u003eThe three human studies included participants with differing characteristics and cancer types. All three clinical trials investigated DSF as a combination therapy with chemotherapy or/and radiation therapy (Huang et al. 2019; Huang et al. 2018; You et al. 2019), while two studies reported on adverse events (Huang et al. 2019; Huang et al. 2018).\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEeffects of disulfiram on PFS and OS from human studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"51\"\u003e\n\u003cp\u003eReference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"41\"\u003e\n\u003cp\u003eCountry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"59\"\u003e\n\u003cp\u003eStudy design\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eStudy participants\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eStudy protocol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003eOS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eAdverse events\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"51\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003eHuang, et al\u003c/p\u003e\n\u003cp\u003e(39)\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"41\"\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003eUSA\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"59\"\u003e\n\u003cp\u003ePhase II,\u003c/p\u003e\n\u003cp\u003eopen-label, single-arm study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eRecurrent GBM who had developed unequivocal progression after RT and concurrent TMZ as per \"the RANO criteria while receiving adjuvant TMZ or within 3 months from the last dose of TMZ\u0026rdquo;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eDSF 80 mg and Cu Gluconate1.5 mg TID by mouth approximately 4\u0026ndash;8h\u003c/p\u003e\n\u003cp\u003eapart.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e7.1 months\u003c/p\u003e\n\u003cp\u003e(95% CI: 5.8\u0026ndash;8.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.7 months\u003c/p\u003e\n\u003cp\u003e(95% CI: 1.4\u0026ndash;1.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eNausea/vomiting (17%) followed by dizziness (9% grade ),Only one patient (4%) had a possible DLT with grade three elevated alanine transaminase on day 31, which required study therapy to be held. The liver function test subsequently recovered after 4 weeks.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"51\"\u003e\n\u003cp\u003eHuang, et al\u003c/p\u003e\n\u003cp\u003e(40)\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"41\"\u003e\n\u003cp\u003eUSA\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"59\"\u003e\n\u003cp\u003ePhase I,\u003c/p\u003e\n\u003cp\u003eopen-label, single-arm, single-institution study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eAdjuvant TMZ in newly diagnosed adult GBM patients after standard chemoradiotherapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e7 patients at DSF 500 mg per day 5 patients at DSF 1000 mg per day, 6 patients at DSF 500 mg per day with Cu 2 mg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e14.0 months\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(95% CI 8.3\u0026ndash;19.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e4.5 months\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(95% CI 0.8\u0026ndash;8.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eone with delirium after 1.6 months (without Cu),one with motor neuropathy after 2.6 months (without Cu),one with diarrhea and nausea after 0.5 months (with Cu),All symptoms resolved shortly after dose reduction.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"51\"\u003e\n\u003cp\u003eNechushtan, et al (41)\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"41\"\u003e\n\u003cp\u003eIsrael\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"59\"\u003e\n\u003cp\u003ephase II, multicenter randomized double-blinded study\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eNewly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time \u0026ldquo;wet IIIb\u0026rdquo; (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003econtrols: six cycles of cisplatin and vinorelbine (plus placebo tablets),\u003c/p\u003e\n\u003cp\u003eexperimental groups: the same plus disulfiram (40mg three times daily).\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e10.0 versus 7.1 months\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e5.9 versus 4.9 months\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e_\u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003cp\u003e \u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\" width=\"51\"\u003e\n\u003cp\u003eAbbreviations: GBM, glioblastoma; NSCLC, non-small cell lung cancer; TMZ, temozolomide; TID, three times per day; DLT, dose-limiting toxicity; RANO, Radiologic Assessment in Neuro-Oncology.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eOutcomes\u003c/h2\u003e\n\u003cp\u003eThree cell lines and one animal study showed that treatment with DSF as a single agent induced apoptosis and increased the rate of tumor inhibition (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014; Choi et al. 2015). Although the sensitivity between the various cell lines varied, dose-dependency was consistently observed.\u003c/p\u003e\n\u003cp\u003eThe concentration-dependent increase in apoptosis and tumor inhibition rates was augmented by a combination therapy of DSF adding metal ions [copper (Cu), silver (Ag)] in 10 in vitro (Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Guo et al. 2019; Yang et al. 2017; Han et al. 2013; Nechushtan et al. 2015) and three in vivo studies (Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015). The synergistic effect of Cis, DOX, TMZ, PTX, Gy, and DSF in induced apoptosis was significantly higher than that of DSF or Cis or DOX or TMZ or Gy alone (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Albers et al. 2014; Zhao et al. 2015; Nechushtan et al. 2015) Tumor cell growth was significantly inhibited when DSF, chemotherapy, and radiation therapy were used simultaneously, as shown in the examined in vivo studies (Ji et al. 2019; Tao et al. 2018;. Choi et al. 2015; Zhou et al. 2018).\u003c/p\u003e\n\u003cp\u003eCompared with free molecule, DSF encapsulated with nanomaterials significantly induced selective death-dependent apoptosis, especially in acidic conditions (pH = 6.5) in cancer cell lines. Eleven animal studies demonstrated that DSF modified by particular nanomaterials increased the tumor inhibition rate and that the anticancer activity was more obvious when chemotherapy (Cis) was combined with nanoencapsulated DSF (Song et al. 2016).\u003c/p\u003e\n\u003cp\u003eChanges in body weight during the whole study period were analyzed in nine animal studies. With the exception of three reports of weight changes in DSF-treated or DSF-modified groups (Ji et al. 2019; Fasehee et al. 2016; Cheriyan et al. 2018), other studies recorded that there was no noticeable body weight loss after DSF treatment or no significant difference in body weight changes across different groups (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), which indicated that there was no major toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015).\u003c/p\u003e\n\u003cp\u003eMany clinical trials have mentioned the use of DSF for solid tumors (www.clinicaltrials.gov). One study clearly analyzed the difference in PFS (5.9 versus 4.9 months) and OS (10.0 versus 7.1 months) between control and experimental groups (Nechushtan et al. 2015). PFS and OS both improved in the experimental groups. Two studies described PFS and OS of the entire research cohort, and the treatment efficacy seemed to be in contrast to historical data (Huang et al. 2019; Huang et al. 2018). Our systemic review included two single-arm trials in glioblastoma (GBM) patients and a randomized controlled trial in NSCLC patients. Although the two single-arm clinical trials did not compare treatment with a control group, positive effects were observed; e.g., a 40-year-old woman with unmethylated isocitrate dehydrogenase wild-type GBM had good health without any signs of tumor recurrence 33 months after study initiation.\u003c/p\u003e\n\u003cp\u003eAmong the reported adverse effects, none were serious, and they were of Grade 2-3. Adverse effects were reported in two studies and included diarrhea, nausea, dizziness, vomiting, motor neuropathy, and elevated alanine transaminase levels. Symptoms resolved quickly when the dose was reduced (Huang et al. 2019; Huang et al. 2018).\u003c/p\u003e\n\u003cp\u003eAll three studies show that DSF is safe and seems to prolong survival of cancer patients. Because of individual differences in patients, the response to DSF was also varied (Huang et al. 2019; Huang et al. 2018; Nechushtan et al. 2015) .The optimal concentration and sensitivity type should be further explored by in vitro and animal studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDSF is decomposed into diethyldithiocarbamate in the body and exhibits anticancer activities (Ekinci et al. 2013). Considering that the loss of cellular proliferation control leads to the development of cancer, effective clinical therapies of cancer have been developed based on the principle of inducing apoptosis (D'Arcy et al. 2019). In the included animal studies, the tumor inhibition rate was utilized to evaluate antitumor efficiency by calculating tumor volume. Most studies included in this review revealed enhanced apoptosis and tumor inhibition rates with DSF treatment.\u003c/p\u003e\n\u003cp\u003eIn recent years, metal-based complexes have been reported to exhibit anticancer activity (Schmitt et al. 2017). Silver complexes demonstrate anti-tumor activity and display low toxicity in humans. The mechanism of action is related to their interaction with nucleic acids and proteins (Banti et al. 2013). Metabolites of DSF chelate with metal ions, leading to alterations in the intracellular levels of metal ions, enhancement of oxidative stress, inhibition of the activities of superoxide dismutase or matrix metalloproteinases, inactivation of essential sulfhydryl groups by protein carbamoylation, and alteration of cancer cell invasion, tumor angiogenesis, and metastasis (Agarwa et al. 1986; Salem et al. 2015). The observation that the combination of DSF with metal ions (Cu, Ag) leads to enhanced anticancer effectiveness is in accordance with the observations of \u003cem\u003ein vitro\u003c/em\u003e and animal experiments.\u003c/p\u003e\n\u003cp\u003eThe additive/synergistic action of DSF with other chemotherapy agents in inhibiting tumor cell growth and cytotoxicity is mediated through the enhancement of cellular oxidative stress, inhibition of P glycol-protein (P-gp) activity, and dysregulation of the NF-\u0026kappa;B signaling pathway (Yang et al. 2019; Majera et al. 2019; Calderon et al. 2019).\u003c/p\u003e\n\u003cp\u003eIn the examined studies, anti-tumor activity, as evidenced by higher apoptosis and tumor inhibition rates, was enhanced with DSF-NPs in various ways. At the pH of 7.4, the half-life of DSF is 1-1.5 min (Agarwa et al. 1986). The half-life was improved by nanomaterial packaging of DSF, with the anti-tumor effects increasing under acidic conditions (pH = 6.5) (Miao et al. 2018). DSF-NPs enhanced cellular uptake, induced high levels of reactive oxygen species, activated the MAP-kinase pathway, sustained drug supply, and blocked copolymer micelles, such as the P-gp inhibitor (Guo et al. 2019; Huo et al. 2017; Chen et al. 2018). Evidence supports that DSF-NPs ameliorate the instability and low treatment efficacy of free DSF.\u003c/p\u003e\n\u003cp\u003eAlthough our results may be more reliable than those of single studies, the present study has certain limitations. First, only articles published in English and Chinese were included; the non-inclusion of articles published in other languages may have had an effect on the results. Second, only four indicators were systematically evaluated, while others were not. Finally, no quality evaluation was conducted, and the majority of studies were animal and cell experiments; thus, the translation of these results to benefits in the clinic needs to be determined.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this systematic review provides evidence of the antineoplastic activity of DSF \u003cem\u003ein vitro\u003c/em\u003e, in \u003cem\u003ein vivo\u003c/em\u003e animal models, and in humans. Many studies have investigated the antineoplastic activity of DSF, with most demonstrating its effectiveness and safety. However, caution is required when interpreting these results because the majority of evidence stems from \u003cem\u003ein vivo\u003c/em\u003e or \u003cem\u003ein vitro\u003c/em\u003e studies. Administration of DSF as a combination therapy or as a nanoparticle-encapsulated molecule seems to enhance its effectiveness, and these findings may serve as the basis for designing clinical studies of DSF in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eAll authors read and approved the final version of this article. Ling Wang conceptualized the review, conducted the literature search, and was responsible for data extraction, data analysis, and for writing the original draft of this manuscript. Cong Zhou was responsible for data extraction. Run Wan conducted the literature search and served as an independent reviewer of the data extracted from the studies, responsible for solving any inconsistencies between Ling Wang and Cong Zhou. Yang Yu and Maswikiti Ewetse Paul contributed to the analysis and interpretation of study data. Yumin Li conceptualized the review, supervised the process, and was responsible for project administration and manuscript review.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China\u003c/p\u003e\n\u003cp\u003e(Grant No. 31770537) and the International Science and Technology Cooperation Project of Gansu Province (Grant No. 18YF1WA113).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eDisclosure statement\u003c/h2\u003e\n\u003cp\u003eLing Wang, Yang Yu, Cong Zhou, Run Wan, Maswikiti Ewetse Paul, and Yumin Li declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbuSerie MM, El-Rashidy FH (2017) In Vitro Collapsing Colon Cancer Cells by Selectivity of Disulfiram-Loaded Charge Switchable Nanoparticles Against Cancer Stem Cells. 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Recent Pat Anticancer Drug Discov 14(2):113-132.\u003c/li\u003e\n\u003cli\u003eEneanya DI, Bianchine JR, Duran DO et al (1981) The actions of metabolic fate of disulfiram. Annu Rev Pharmacol Toxicol 21575-596.\u003c/li\u003e\n\u003cli\u003eFasehee H, Dinarvand R, Ghavamzadeh A et al (2016) Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles: in vitro and in vivo investigations. J Nanobiotechnology 1432.\u003c/li\u003e\n\u003cli\u003eGotzsche PC (1988) Ditiocarb in HIV infection. Lancet 2(8618):1024.\u003c/li\u003e\n\u003cli\u003eGuo F, Yang Z, Kulbe H et al (2019) Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation. Biomed Pharmacother 118109371.\u003c/li\u003e\n\u003cli\u003eHan J, Liu L, Yue X et al (2013) A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts.Toxicol Appl Pharmacol 273(3):477-483.\u003c/li\u003e\n\u003cli\u003eHuang J, Campian JL, Gujar AD et al (2018) Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma. J Neurooncol 138(1):105-111.\u003c/li\u003e\n\u003cli\u003eHuang J, Chaudhary R, Cohen AL et al (2019) A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma. J Neurooncol 142(3):537-544.\u003c/li\u003e\n\u003cli\u003eHuo Q, Zhu J, Niu Y et al (2017) pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer. Int J Nanomedicine 128631-8647.\u003c/li\u003e\n\u003cli\u003eJi YB, Liu B, Yu RQ et al (2019) Preparation of disulfiram naonosuspensions and their anti-tumor\u003c/li\u003e\n\u003cli\u003eefficacy in vitro and in vivo. Acta Pharmaceutica Sinica 54(3): 565 \u0026minus;573.\u003c/li\u003e\n\u003cli\u003eKaitin KI (2010) Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther 87(3):356-361.\u003c/li\u003e\n\u003cli\u003eKim JY, Cho Y, Oh E et al (2016) Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer. Cancer Lett 379(1):39-48.\u003c/li\u003e\n\u003cli\u003eLewison EF (1977) Spontaneous regression of breast cancer. Prog Clin Biol Res 1247-53.\u003c/li\u003e\n\u003cli\u003eMajera D, Skrott Z, Bouchal J et al (2019) Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram. Prostate 79(4):352-362.\u003c/li\u003e\n\u003cli\u003eMiao L, Su J, Zhuo X et al (2018) mPEG5k- b-PLGA2k/PCL3.4k/MCT Mixed Micelles as Carriers of Disulfiram for Improving Plasma Stability and Antitumor Effect in Vivo. Mol Pharm 15(4):1556-1564.\u003c/li\u003e\n\u003cli\u003eMoher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006-1012.\u003c/li\u003e\n\u003cli\u003eNechushtan H, Hamamreh Y, Nidal S et al (2015) A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist 20(4):366-367.\u003c/li\u003e\n\u003cli\u003ePeng X, Pan Q, Zhang B et al (2019) Highly Stable, Coordinated Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate for Combinational Chemo/Chemodynamic Therapy of Cancer. Biomacromolecules 20(6):2372-2383.\u003c/li\u003e\n\u003cli\u003eRezkk Y, Yang S, Bai K et al (2013) Disulfiram\u0026rsquo;s antineoplastic effects on ovarian cancer bulk tumor cells and the stem cell population: A study in ovarian cancer cell lines and in rodents. \u003ca href=\"https://www.sciencedirect.com/science/journal/00908258\"\u003eGynecologic Oncology\u003c/a\u003e 130(1):e135-e136.\u003c/li\u003e\n\u003cli\u003eSalem K, McCormick ML, Wendlandt E et al (2015) Copper-zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma. Redox Biol 423-33.\u003c/li\u003e\n\u003cli\u003eSchmitt SM, Frezza M \u0026amp; Dou QP (2012) New applications of old metal-binding drugs in the treatment of human cancer. Front Biosci (Schol Ed) 4375-391.\u003c/li\u003e\n\u003cli\u003eSharma V, Verma V, Lal N et al (2016) Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor beta. Mol Carcinog 55(11):1843-1857.\u003c/li\u003e\n\u003cli\u003eSong W, Tang Z, Lei T et al (2016a) Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy. Nanomedicine 12(2):377-386.\u003c/li\u003e\n\u003cli\u003eSong W, Tang Z, Shen N et al (2016b) Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. Control Release 23194-102.\u003c/li\u003e\n\u003cli\u003eSuh JJ, Pettinati HM, Kampman KM et al (2006) The status of disulfiram: a half of a century later. J Clin Psychopharmacol 26(3):290-302.\u003c/li\u003e\n\u003cli\u003eTao X, Gou J, Zhang Q et al (2018) Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles. Biomater Sci 6(7):1869-1881.\u003c/li\u003e\n\u003cli\u003eWang C, Yang J, Han H et al (2017) Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer. Int J Nanomedicine 12827-837.\u003c/li\u003e\n\u003cli\u003eWu L, Meng F, Dong L et al (2019) Disulfiram and BKM120 in Combination with Chemotherapy Impede Tumor Progression and Delay Tumor Recurrence in Tumor Initiating Cell-Rich TNBC. Sci Rep 9(1):236.\u003c/li\u003e\n\u003cli\u003eWu X, Xue X, Wang L et al (2018) Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. Eur J Pharmacol 8271-12.\u003c/li\u003e\n\u003cli\u003eYang Y, Li M, Sun X et al (2017) The selective cytotoxicity of DSF-Cu attributes to the biomechanical properties and cytoskeleton rearrangements in the normal and cancerous nasopharyngeal epithelial cells. Int J Biochem Cell Biol 8496-108.\u003c/li\u003e\n\u003cli\u003eYang Y, Zhang K, Wang Y et al (2016) Disulfiram chelated with copper promotes apoptosis in human breast cancer cells by impairing the mitochondria functions. Scanning 38(6):825-836.\u003c/li\u003e\n\u003cli\u003eYang Z, Guo F, Albers AE et al (2019) Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother 113108727.\u003c/li\u003e\n\u003cli\u003eYou SY, Rui W, Chen ST et al (2019) Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate. Biochem Biophys Res Commun 513(4):891-897.\u003c/li\u003e\n\u003cli\u003eZhang L, Tian B, Li Y et al (2015) A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding TAT Peptide-Modified Lipid Nanocapsules for Use in Tumor Therapy. ACS Appl Mater Interfaces 7(45):25147-25161.\u003c/li\u003e\n\u003cli\u003eZhao Y, Xiao Z, Chen W et al (2015) Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression. Mol Med Rep 12(2):2313-2322.\u003c/li\u003e\n\u003cli\u003eZhou L, Yang L, Yang C et al (2018) Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram for Improving Synergistic Antitumor Effect In Vivo. Pharm Res 35(7):147.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"disulfiram, apoptosis rate, tumor inhibition rate, progression-free survival, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-140063/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-140063/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and objectives:\u003c/strong\u003e Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Several preclinical and clinical studies have examined the potential of repurposing disulfiram (DSF) as an anticancer treatment. This systematic review aimed to assess evidence regarding the antineoplastic activity of DSF in \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e models, as well as in humans.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eTwo authors independently conducted this systematic review of English and Chinese articles from the PubMed, Embase, and the Cochrane Library databases up to July 2019. Eligible \u003cem\u003ein vitro\u003c/em\u003e studies needed to include assessments of the apoptosis rate by flow cytometry using annexin V/propidium iodide, and studies in animal models and clinical trials needed to examine tumor inhibition rates, and progression-free survival (PFS) and overall survival (OS), respectively. Data were analyzed using descriptive statistics.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Overall, 35 studies, i.e., 21 performed \u003cem\u003ein vitro\u003c/em\u003e, 11 based on animal models, and three clinical trials, were finally included. \u003cem\u003eIn vitro\u003c/em\u003e and animal studies indicated that DSF was associated with enhanced apoptosis and tumor inhibition rates. Human studies showed that DSF prolongs PFS and OS. The greatest anti-tumor activity was observed when DSF was used as combination therapy or as a nanoparticle-encapsulated molecule.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e This systematic review provides evidence regarding the anti-tumor activity of DSF \u003cem\u003ein vitro\u003c/em\u003e, in animals, and in humans and indicates the optimal forms of treatment to be evaluated in future research.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Anticancer Effects of Disulfiram: A Systematic Review of in Vitro, Animal, and Human Studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-15 17:00:38","doi":"10.21203/rs.3.rs-140063/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-07-26T09:41:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-07-16T00:00:00+00:00","index":2,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nI would like to mention the follwoing comments:\n\n1- Introduction: The reference of first sentence (in frist paragraph) is missing.\n\n2- Intrdoction: First paragraph: Second sentence: It is better to mention worldwise.\n\n3- Introduction: It is better to explain about DSF in the frist place.\n\n4- Method: July 2019: First , middle of end of July?\n\n5- Method: Pre-designed structure: Was it excel or another program?\n\n6- Mathod: Type of studies are different. It is difficult for reviewer (with familiraity with human research) to check the studies on animals or cells. How did this problem consider?\n\n7- I am wondering about the reliability of comparison of in vitro, animal and human studies. Is it reliable?\n\n8- What will the comparison of in vitro, animal and human studies add to the science?\n\n9- The title of figures must be at the botton of figures.\n\n10- Figure 1: The number of studeis must be divided into 3 parts (in vitro, animal, human) in all boxes.\n\nGood Luck\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article of importance in its field that should be highlighted to relevant networks**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2021-07-04T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\nSYSR-D-20-01036\n\n1- A little more detail is required about DFS and it mechanism of action or significance to justify the study better in the abstract.\n2- The three sets of criteria for inclusion were apoptosis in cell culture, animal studies, and clinical trials, or were these individually a criterion for 3 separate systematic review studies?\nIt is not clear from the abstract? Although then you make this more clear in the results section of the abstract and in the rest of the paper.\n3- What specific cancer was studied? It becomes clear later in the paper that it is not a specific cancer type.\n4- It may have been a better idea to only focus on one type of study (in vitro, in vivo, or clinical trials) since the 3 categories have led to less focus. It is rather unusual to focus on 3 different topics.\n5- The introduction includes side effects and potential benefits of DFS that justify this study. This has not been covered sufficiently.\n6- Search strategy: how about \"tumour\". You could try this to see if any papers have been missed.\n7- The xenografting experiment in 10 cases was performing using cancer cells lines while one used in situ tumour models (primary tumour). These would be very different experiments and perhaps not very comparable.\n8- The scarcity of the studies in general (35 in total) and the fact that they are performed on different cancers, may make any specific conclusions difficult.\n9- It would be good to summarise your findings (disuccsed in the discussion section) in a table.\n10- The side effects have been mentioned in the results but could be expanded.\n11- Page 9 of the manuscript, lines 3-5 please insert a reference to the in vitro animal experiments you are referring to.\n12- Another limitation is the type of cancer that should be included in the limitation section of the discussion.\n13- In figure 1, why were the 856 records excluded, please explain better.\n14- The results of table 1 could be better discussed in terms of what drug concentration was most effective. This can be expanded in the discussion.\n15- The in vivo xenograft studies can be better interpreted as well, what doses significantly increased EFS or decreased tumour burden. This applies to table 3. This can be expanded in the discussion.\n16- Why are there 2 sets of tables \"1-3\"? Consider renaming them.\n17- The conclusion of the study needs more expansion.\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **'I declare that I have no competing interests'**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2021-07-03T01:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-07-03T00:00:00+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-07-03T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-06-22T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-06-07T22:18:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-06-06T23:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-01-03T22:36:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-12-30T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f16d647c-6122-4789-a44d-d7d6ad51d1bc","owner":[],"postedDate":"January 15th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":1906688,"name":"Health Economics \u0026 Outcomes Research"},{"id":1906689,"name":"Scientific Communication"}],"tags":[],"updatedAt":"2021-11-11T22:48:57+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-15 17:00:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-140063","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-140063","identity":"rs-140063","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}