Combining same-target drugs exhibits additive efficacy with minimal toxicity

Combining same-target drugs exhibits additive efficacy with minimal toxicity | 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 Biological Sciences - Article Combining same-target drugs exhibits additive efficacy with minimal toxicity Shao-Qing Cai, Yi Wang, Feng Xu, Qian Zhao, Hong-Fu Li, Weijing Cai, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4822017/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Drug toxicity is a major concern in medicine, and toxicity is an unresolved obstacle to the efficacy of chemotherapy drugs for cancer. Based on our ‘additive effect’ and ‘toxicity scattering effect’ hypothesis, we propose a unique drug-combination strategy to overcome drug toxicities: combining 8–10 drugs that act on the same target at ineffective doses (much lower than their usual doses) to dramatically reduce the toxicity of each drug without weakening the efficacy of the combination. Using this strategy, we developed an anticancer combination of 8 drugs (topoisomerase II inhibitors); each drug was included at 7.7%–19.5% of its minimum effective dose. This combination prolonged life by 92.8% in ascites tumour-bearing mice and inhibited tumour growth by 54.3% in solid tumour-bearing mice, without causing mortality or detectable liver, cardiac, or renal toxicity. At an average of 1/3 of the combination dose, each drug alone resulted in ineffective tumour inhibition (only 24.6%–34.5% reduction) but caused a 10%–50% mortality. As number of drugs in the combination increased from 1 to 4 to 8, the dose of each drug and the overall toxicity progressively decreased. Combinations of four or six topoisomerase II inhibitors at low concentrations inhibited the proliferation of cancer cell lines and the activity of topoisomerase II, revealing an evident additive effect on the same target. These results demonstrate the significant advantage of this strategy in reducing toxicity. Although this strategy violates drug use principles, it may be a breakthrough in reducing toxicity and improving cancer treatment. This strategy can also be applied to other diseases with high drug toxicity. Health sciences/Health care/Therapeutics/Adverse effects Biological sciences/Drug discovery/Drug safety Biological sciences/Cancer/Cancer therapy/Drug development Health sciences/Diseases/Cancer/Cancer therapy/Chemotherapy Health sciences/Medical research/Translational research Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SMSIGuide240729.docx SI Guide SupplementaryInformation240729.pdf Supplementary information note，discussion, figures, and tables Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4822017","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":342798930,"identity":"24bab7ca-6199-4511-b319-778faf566bdc","order_by":0,"name":"Shao-Qing Cai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYLCChIoDzGAGD/FazpCshbHtAAPxWuTbkx9+eDjvDrvujATGB2/bGOTNCWkxOPPMWCJx2zNmsxsJzIZz2xgMdzYQ0iKRwwDUchikhU2at40hweAAIYfNyGH+kTgHrIX9N1FaGG7ksEkkNkBsYSZKC9AvZhYJx4B+OfOwWXLOOQnDDQQd1p78+OaPmjvJZseTD354U2YjT9hhDAlgMhkYOw1AWoKgergWO2KUjoJRMApGwQgFALqGQkBg5+3ZAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-7643-4786","institution":"Peking University","correspondingAuthor":true,"prefix":"","firstName":"Shao-Qing","middleName":"","lastName":"Cai","suffix":""},{"id":342798931,"identity":"302dfec6-4746-4c7a-a462-e0a5ed616828","order_by":1,"name":"Yi Wang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Wang","suffix":""},{"id":342798932,"identity":"7547d291-c024-40db-a07e-3bbb9685a291","order_by":2,"name":"Feng Xu","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Xu","suffix":""},{"id":342798933,"identity":"19dc0700-f0e3-43be-bdd8-5dbd02cf69b2","order_by":3,"name":"Qian Zhao","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Zhao","suffix":""},{"id":342798934,"identity":"93d964fe-5326-413a-a6c8-f4b414d4dcac","order_by":4,"name":"Hong-Fu Li","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Hong-Fu","middleName":"","lastName":"Li","suffix":""},{"id":342798935,"identity":"02ad93e3-8c60-415c-88fd-67da6a26d125","order_by":5,"name":"Weijing Cai","email":"","orcid":"","institution":"College of Pharmacy, University of Florida ","correspondingAuthor":false,"prefix":"","firstName":"Weijing","middleName":"","lastName":"Cai","suffix":""},{"id":342798936,"identity":"f717f155-0582-42b3-9dd0-5b406c2686c2","order_by":6,"name":"Jing-Rong Cui","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Jing-Rong","middleName":"","lastName":"Cui","suffix":""},{"id":342798937,"identity":"8b958e54-a127-442e-b00f-71fee43125f8","order_by":7,"name":"Li-Jia Liu","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Li-Jia","middleName":"","lastName":"Liu","suffix":""},{"id":342798938,"identity":"74ac6d6a-6330-40f1-9d9e-bafdefc02cbf","order_by":8,"name":"Yi-Fan Zhang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Yi-Fan","middleName":"","lastName":"Zhang","suffix":""},{"id":342798939,"identity":"e6298d9a-94d5-4727-9aaa-4c34e1467bb0","order_by":9,"name":"Chao-Qun Wang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Chao-Qun","middleName":"","lastName":"Wang","suffix":""},{"id":342798940,"identity":"19e7bdb2-4158-49ee-a3c4-2c3ddc10e694","order_by":10,"name":"Xing-Xin Yang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Xing-Xin","middleName":"","lastName":"Yang","suffix":""},{"id":342798941,"identity":"7f1ae171-48a4-49c2-af7e-116eed54a5e6","order_by":11,"name":"Ping Yang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Yang","suffix":""},{"id":342798942,"identity":"c329f7a4-9326-4ac1-a74d-9020a17c8465","order_by":12,"name":"Zhi-Wei Yang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Zhi-Wei","middleName":"","lastName":"Yang","suffix":""},{"id":342798943,"identity":"b11b8246-d0d5-4471-9460-772498f3336d","order_by":13,"name":"Ming-Ying Shang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Ming-Ying","middleName":"","lastName":"Shang","suffix":""},{"id":342798944,"identity":"8c3ce9a8-ab42-4759-ab77-627901915d61","order_by":14,"name":"Guang-Xue Liu","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Guang-Xue","middleName":"","lastName":"Liu","suffix":""},{"id":342798945,"identity":"5d18b418-0729-4888-bbb6-2546c3e179e9","order_by":15,"name":"Xuan Wang","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Peking University Health Science Centre","correspondingAuthor":false,"prefix":"","firstName":"Xuan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-07-29 12:31:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4822017/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4822017/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63928217,"identity":"e01c2caf-4a91-4f04-ac47-a21597b7f33d","added_by":"auto","created_at":"2024-09-04 00:19:14","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6986339,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Maintext240729.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4822017/v1_covered_6c7b9ff5-495e-44ab-91a1-01313607091f.pdf"},{"id":63928008,"identity":"224ad8c5-9199-44f9-a530-c337e20000fc","added_by":"auto","created_at":"2024-09-04 00:11:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28321,"visible":true,"origin":"","legend":"SI Guide","description":"","filename":"SMSIGuide240729.docx","url":"https://assets-eu.researchsquare.com/files/rs-4822017/v1/2421758a445f83c0c6e6f93d.docx"},{"id":63928009,"identity":"bea0e98a-b41f-410d-af75-8d9af5bdb3d8","added_by":"auto","created_at":"2024-09-04 00:11:08","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2477050,"visible":true,"origin":"","legend":"Supplementary information note\u0026#xFF0C;discussion, figures, and tables","description":"","filename":"SupplementaryInformation240729.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4822017/v1/f39a872cecc2029cac4d690a.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Combining same-target drugs exhibits additive efficacy with minimal toxicity","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4822017/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4822017/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Drug toxicity is a major concern in medicine, and toxicity is an unresolved obstacle to the efficacy of chemotherapy drugs for cancer. Based on our ‘additive effect’ and ‘toxicity scattering effect’ hypothesis, we propose a unique drug-combination strategy to overcome drug toxicities: combining 8–10 drugs that act on the same target at ineffective doses (much lower than their usual doses) to dramatically reduce the toxicity of each drug without weakening the efficacy of the combination. Using this strategy, we developed an anticancer combination of 8 drugs (topoisomerase II inhibitors); each drug was included at 7.7%–19.5% of its minimum effective dose. This combination prolonged life by 92.8% in ascites tumour-bearing mice and inhibited tumour growth by 54.3% in solid tumour-bearing mice, without causing mortality or detectable liver, cardiac, or renal toxicity. At an average of 1/3 of the combination dose, each drug alone resulted in ineffective tumour inhibition (only 24.6%–34.5% reduction) but caused a 10%–50% mortality. As number of drugs in the combination increased from 1 to 4 to 8, the dose of each drug and the overall toxicity progressively decreased. Combinations of four or six topoisomerase II inhibitors at low concentrations inhibited the proliferation of cancer cell lines and the activity of topoisomerase II, revealing an evident additive effect on the same target. These results demonstrate the significant advantage of this strategy in reducing toxicity. Although this strategy violates drug use principles, it may be a breakthrough in reducing toxicity and improving cancer treatment. This strategy can also be applied to other diseases with high drug toxicity.","manuscriptTitle":"Combining same-target drugs exhibits additive efficacy with minimal toxicity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-04 00:11:03","doi":"10.21203/rs.3.rs-4822017/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6ef5c00f-cf69-44d9-a550-fe410b35670d","owner":[],"postedDate":"September 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":36319527,"name":"Health sciences/Health care/Therapeutics/Adverse effects"},{"id":36319528,"name":"Biological sciences/Drug discovery/Drug safety"},{"id":36319529,"name":"Biological sciences/Cancer/Cancer therapy/Drug development"},{"id":36319530,"name":"Health sciences/Diseases/Cancer/Cancer therapy/Chemotherapy"},{"id":36319531,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2024-09-04T00:11:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-04 00:11:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4822017","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4822017","identity":"rs-4822017","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}