Effects of amifostine on endometriosis, comparison with N-acetyl cysteine, and leuprolide as a new treatment alternative: a randomized controlled trial

Purpose To assess the effects of amifostine, N-acetyl cysteine (NAC), and leuprolide as a scavenger in a rat endometriosis model.

This is a prospective randomized animal study. Setting The Animal Laboratory of Medical University. Animals 40 rats were used for transplantation of an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. After allowing 3 weeks for growth, laparotomies were performed to check the implants. Then animals were randomized into four groups: Group I amifostine (200 mg/day loading dose after 20 mg/kg/day, p.o.); Group II NAC (200 mg/day, p.o.); Group III leuprolide acetate 1 mg/kg single dose, sc; and Group IV (controls) no medication. Three weeks later, implants were evaluated morphologically. Serum and peritoneal TNF-alpha levels were evaluated. The transmission electron microscopic examination of the peritoneal samples and ovaries was also performed.

Leuprolide acetate, amifostine and NAC caused significant decreases in the mean implant areas and significant decreases in serum and peritoneal TNF-alpha levels. On comparing all groups, these reductions were higher in Group II. According to the transmission electron microscopic findings, leuprolide seems to be protecting normal structure of peritoneum best when compared to the other groups.

Amifostine, NAC and leuprolide caused regression of endometriosis in this experimental rat model by a yet unsettled mechanism. Similar content being viewed by others

Wheeler JM (1989) Epidemiology of endometriosis-associated infertility. J Reprod Med 34:41–46 Matorras R, Rodiquez F, Pijoan JI, Ramon O, Gutierrez DT (1995) Rodriguez- Escudero F Epidemiology of endometriosis in infertile women. Fertil Steril 63:34–38 Portz DM, Elkins TE, White R, Warren J (1991) Adadevoh S and Randolph J Oxygen free radicals and pelvic adhesion formation: I. Blocking oxygen free radical toxicity to prevent adhesion formation in an endometriosis model. Int J Fertil 36:39–42 Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S (1998) Evidence for oxidatively modified lipid-protein complexes in endometrium and endometriosis. Fertil Steril 69:1092–1094 Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77:861–870 Jackson LW, Schisterman EF, Dey-Rao R, Browne R, Armstrong D (2005) Oxidative stress and endometriosis. Hum Reprod 20:2014–2020 Zeller JM, Henig I, Radwanska E, Dmowski WP (1987) Enhancement of human monocyte and peritoneal macrophage chemiluminescence activities in women with endometriosis. Am J Reprod Immunol Microbiol 13:78–82 Murphy AA, Santanam N, Parthasarathy S (1998) Endometriosis: a disease of oxidative stress? Semin Reprod Endocrinol 16:263–273 Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S (1998) Macrophage scavenger receptor(s) and oxidatively modified proteins in endometriosis. Fertil Steril 69:1085–1094 Vinatier D, Cosson M, Dufour P (2000) Is endometriosis an endometrial disease ? Eur J Obstet Gynecol Reprod Biol 91:113–125 Van Der Vijgh WJF, Korst AEC (1996) Amifostine (ethyol®): pharmacocinetic and pharmacodynamic effects in vivo. Eur J Cancer 32:26–30 Valerıa S, Francıs J (1999) Gıles the potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica 84:1035–1042 Meister A, Anderson ME (1983) Glutathione. Annu Rev Biochem 52:711–760 Slusser SO, Grotyohann LW, Martin LF (1990) Scaduto RC glutathione catabolism by the ischemic rat kidney. Am J Physiol 258:1546–1553 Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, Agarwal A (2002) Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 17:426–431 Iwabe T, Harada T, Terakawa N (2002) Role of cytokines in endometriosis-associated infertility. Gynecol Obstet Invest 53:19–25 Küpker W, Felberbaum R, Bauer O, Diedrich K (1996) Significance of tumour necrosis factor alpha (TNF-alpha) in endometriosis. Geburtshilfe Frauenheilkd 56:239–242 Richter ON, Dorn C, Rösing B, Flaskamp C, Ulrich U (2005) Tumor necrosis factor alpha secretion by peritoneal macrophages in patients with endometriosis. Arch Gynecol Obstet 271:143–147 Galo S, Zúbor P, Szunyogh N, Kajo K, Macháleková K, Biringer K, Visnovský J (2005) TNF-alpha serum levels in women with endometriosis: prospective clinical study. Ceska Gynekol 70:286–290 Yavuz E, Oktem M, Esinler I, Arat Toru S, Zeyneloglu HB (2007) Genistein causes regression of endometriotic implants in the rat model. Fertil Steril 88:1129–1134 Dogan E, Saygili U, Posaci C, Tuna B, Caliskan S, Altunyurt S, Saatli B (2004) Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril 182:1115–1120 Capizzi RL (1996) Amifostine: the preclinical basis for broadspectrum selective cytoprotection of normal tissues from cytotoxic therapies. Semin Oncol 23:2–17 McCauley DL (1997) Amifostine: a novel cytoprotective agent. Cancer Pract 5:189–191 Foster-Nora JA, Siden R (1997) Amifostine for protection from antineoplastic drug toxicity. Am J Health-Syst Pharm 54:787–800 Valeriote F, Tolen S (1982) Protection and potentiation of nitrogen mustard cytotoxicity by WR-2721. Cancer Res 42:4330–4331 Yuhas JM, Spellman JM, Jordan SW, Pardini MC, Afzal SN, Culo F (1980) Treatment of tumors with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide. Br J Cancer 42:574–585 Yuhas JM, Culo F (1980) Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum (II) by WR-2721 without altering its antitumor properties. Cancer Treat Rep 64:57–64 Griggs JJ (1998) Reducing the toxicity of anticancer therapy: new strategies. Leuk Res 22:27–33 Alberts DS, Speicher LA, Krutzsch M et al (1996) WR-1065, the active metabolite of amifostine (Ethyol®), does not inhibit the cytotoxic effects of a broad range of standard anticancer drugs against human ovarian and breast cancer cells. Eur J Cancer 32:17–20 Kemp G, Rose P, Lurain J et al (1996) Amifostine pretreatment for protection against cyclophosphamideinduced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 14:2101–2112 Dunn TA, Schmoll H-J, Grunwald V, Bokemeyer C, Casper J (1996) Amifostine does not alter the antitumor activity of cisplatin in a pre-clinical model of testicular cancer. Anticancer Drugs 7:795–799 Aviles A, Diaz-Maqueo JC, Talavera A, Garcia EL, Guzman R, Nambo MJ (1997) Bone marrow protection with amifostine in the treatment of high-risk malignant lymphoma. Eur J Cancer 33:1323–1325 Paine GD, Taylor CW, Lopez MHA, Johnson CS, Capizzi RL (1996) Effects of amifostine and paclitaxel on growth of human ovarian carcinoma xenografts in the severe combined immune-deficient mouse: preliminary results. Semin Oncol 2:35–39 Marzatıco F, Porta C, Moronı M, Bertorellı L, Borasıo E, Fınottı N, Pansarasa O, Castagna L (2000) In vitro antioxidant properties of amifostine (WR-2721, Ethol). Cancer Chemother Pharmacol 45:172–176 Ohnıshı ST, Ohnıshı T, Glıck JH, Scheın PS (1992) In vitro study on the antioxidant activities of amifostine (WR-2721). Proc Am Assoc Cancer Res 33:419 Orditura M, Devita F, Roscigno A (1999) Amifostine: a selective cytoprotective agent of normal tissues from chemo-radiotherapy induced toxicity. Oncol Rep 6:1357–1362 Stankıewıcz A, Skrzydlewska E, Makıeła M (2002) Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metab Drug Interact 19:67–82 Stankiewicz A, Skrzydlewska E, Sulkowska M, Sulkowski S (2002) Effect of amifostine on lung oxidative stress after cyclophosphamide therapy. Bull Vet Pulawy 46:87 Stankiewicz E, Skrzydlewska E (2005) Amifostine antioxidant effect on serum of rats treated with Cyclophosphodamide A. Pol J Environ Stud 14:341–346 Shaw LM, Glover D, Turrisi A et al (1988) Pharmacokinetics of WR-2721. Pharmacol Ther 39:195–201 Shaw LM, Turrisi AT, Glover DJ et al (1986) Human pharmacokinetics of WR-2721. Int J Radiat Oncol Biol Phys 12:1501–1504 Korst AEC, Gall HE, Vermorken JB, van der Vijgh WJF (1996) Pharmacokinetics of amifostine and its metabolites in the plasma and ascites of a cancer patient. Cancer Chemother Pharmacol 39:162–166 Utley JF, Seaver N, Newton GL, Fahey RC (1984) Pharmacokinetics of WR-1065 in mouse tissue following treatmentwith WR-2721. Int J Radiat Oncol Biol Phys 10:1525–1528 Shaw LM, Bonner H, Lieberman R (1996) Pharmacokinetic profile of amifostine. Semin Oncol 23:18–22 Cassatt DR, Fazenbaker CA, Kifle G, Bachy CM (2002) Preclinical studies on the radioprotective efficacy and pharmacokinetics of subcutaneously administered amifostine. Semin Oncol 29(6 Suppl 19):2–8 Review Cassatt DR, Fazenbaker CA, Kifle G, Bachy CM (2003) Subcutaneous administration of amifostine (ethyol) is equivalent to intravenous administration in a rat mucositis model. Int J Radiat Oncol Biol Phys 57(3):794–802 Elas M, Parasca A, Grdina DJ, Halpern HJ (2003) Oral administration is as effective as intraperitoneal administration of amifostine in decreasing nitroxide EPR signal decay in vivo. Biochim Biophys Acta 1637:151–155 Ocal K, Avlan D, Cinel I, Unlu A, Ozturk C, Yaylak F, Dirlik M, Camdeviren H, Aydin S (2004) The effect of N-acetyl cysteine on oxidative stress in intestine and bacterial translocation after thermal injury. Burns 30:778–784 Conesa LE, Valero F, Nadal JC et al (2001) N-acetyl-l-cysteine improves renal medullary hypoperfusion in acute renal failure. Am J Physiol 281:730–737 Sehirli AO, Sener G, Satiroglu H, Ayanoglu-Dulger G (2003) Protective effect of N-acetyl cysteine on renal ischemia/reperfusion injury in the rat. J Nephrol 16:75–80 Sato Hideyo, Tamba Michiko, Ishii Tetsuro, Bannai Shiro (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 27:11455–11458 Conflict of interest The authors declare that they have no competing interests. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Onalan, G., Gulumser, C., Mulayim, B. et al. Effects of amifostine on endometriosis, comparison with N-acetyl cysteine, and leuprolide as a new treatment alternative: a randomized controlled trial. Arch Gynecol Obstet 289, 193–200 (2014). https://doi.org/10.1007/s00404-013-2963-0 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00404-013-2963-0