Skip to main content
SpringerLink
Log in

Effects of Amifostine in Combination With Cyclophosphamide on Female Reproductive System

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

This study investigated the cytoprotective effects of amifostine against the adverse effects of cyclophosphamide relying on ovarian cell death markers and the fertilization rate of the surviving follicles as a late outcome of the study. Combined pretreatment of amifostine with cyclophosphamide enabled partial recovery of antiapoptotic messenger RNA (mRNA) expression levels while a decrease in expression of BAX and Casp3 were identified. The pretreatment of amifostine to cyclophosphamide significantly reduced the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive primary and preantral follicles (P < .001 and P < .05, respectively). These findings were comparable with the results obtained from protein expression of cleaved caspase 3. The fertilization rate showed a significant capability of amifostine to improve fertilization potency of oocytes exposed to cyclophosphamide (P < .01). In conclusion, administration of amifostine prior to cyclophosphamide might serve as a promising protocol to improve female fertility.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bukowski R. Cytoprotection in the treatment of pediatric cancer: review of current strategies in adults and their application to children. Med Pediatr Oncol. 1999;32(2):124–134.

    Article  CAS  PubMed  Google Scholar 

  2. Colvin OM. An overview of cyclophosphamide development and clinical applications. Curr Pharm Des. 1999;5(8):555–560.

    CAS  PubMed  Google Scholar 

  3. Wilkinson A. Progress in the clinical application of immunosuppressive drugs in renal transplantation. Curr Opin Nephrol Hyper-tens. 2001;10(6):763–770.

    Article  CAS  Google Scholar 

  4. Meirow D, Assad G, Dor J, Rabinovici J. The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod. 2004;19(6):1294–1299.

    Article  CAS  PubMed  Google Scholar 

  5. Plowchalk DR, Meadows MJ, Mattison DR. Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 2. Effects on uterine structure and function. Reprod Toxicol. 1992;6(5):423–429.

    Article  CAS  PubMed  Google Scholar 

  6. Lopez SG, Luderer U. Effects of cyclophosphamide and buthio-nine sulfoximine on ovarian glutathione and apoptosis. Free Radic Biol Med. 2004;36(11):1366–1377.

    Article  CAS  PubMed  Google Scholar 

  7. Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am. 1998;27(4):927–943.

    Article  CAS  PubMed  Google Scholar 

  8. Kumar R, Biggart JD, McEvoy J, McGeown MG. Cyclophosphamide and reproductive function. Lancet. 1972;1(7762):1212–1214.

    Article  CAS  PubMed  Google Scholar 

  9. Barekati Z, Gourabi H, Valojerdi MR, Yazdi PE. Previous maternal chemotherapy by cyclophosphamide (Cp) causes numerical chromosome abnormalities in preimplantation mouse embryos. Reprod Toxicol. 2008;26(3–4):278–281.

    Article  CAS  PubMed  Google Scholar 

  10. Pydyn EF, Ataya KM. Effect of cyclophosphamide on mouse oocyte in vitro fertilization and cleavage: recovery. Reprod Toxicol. 1991;5(1):73–78.

    Article  CAS  PubMed  Google Scholar 

  11. Ataya KM, Pydyn EF, Sacco AG. Effect of “activated” cyclophosphamide on mouse oocyte in vitro fertilization and cleavage. Reprod Toxicol. 1988;2(2):105–109.

    Article  CAS  PubMed  Google Scholar 

  12. Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004;22(20):4174–4183.

    Article  PubMed  Google Scholar 

  13. Anchan RM, Ginsburg ES. Fertility concerns and preservation in younger women with breast cancer. Crit Rev Oncol Hematol. 2010;74(3):175–192.

    Article  PubMed  Google Scholar 

  14. Kim SS. Fertility preservation in female cancer patients: current developments and future directions. Fertil Steril. 2006;85(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  15. Nguyen NP, Levinson B, Dutta S, et al. Amifostine and curative intent chemoradiation for compromised cancer patients. Anticancer Res. 2003;23(2C):1649–1656.

    CAS  PubMed  Google Scholar 

  16. Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol. 2000;18(19):3339–3345.

    Article  CAS  PubMed  Google Scholar 

  17. Culy CR, Spencer CM. Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs. 2001;61(5):641–684.

    Article  CAS  PubMed  Google Scholar 

  18. Links M, Lewis C. Chemoprotectants: a review of their clinical pharmacology and therapeutic efficacy. Drugs. 1999;57(3):293–308.

    Article  CAS  PubMed  Google Scholar 

  19. Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD, Fahey RC. Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res. 1988;48(13):3634–3640.

    CAS  PubMed  Google Scholar 

  20. Smoluk GD, Fahey RC, Calabro-Jones PM, Aguilera JA, Ward JF. Radioprotection of cells in culture by WR-2721 and derivatives: form of the drug responsible for protection. Cancer Res. 1988;48(13):3641–3647.

    CAS  PubMed  Google Scholar 

  21. List AF, Heaton R, Glinsmann-Gibson B, Capizzi RL. Amifostine protects primitive hematopoietic progenitors against chemotherapy cytotoxicity. Semin Oncol. 1996;23(4 suppl 8):58–63.

    CAS  PubMed  Google Scholar 

  22. Peters GJ, van der Vijgh WJ. Protection of normal tissues from the cytotoxic effects of chemotherapy and radiation by amifostine (WR-2721): preclinical aspects. Eur J Cancer. 1995;31(suppl 1):S1–S7.

    Article  Google Scholar 

  23. Santini V, Giles FJ. The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999;84(11):1035–1042.

    CAS  PubMed  Google Scholar 

  24. Yuhas JM, Culo F. Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum(II) by WR-2721 without altering its antitumor properties. Cancer Treat Rep. 1980;64(1):57–64.

    CAS  PubMed  Google Scholar 

  25. Wasserman TH, Phillips TL, Ross G, Kane LJ. Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFUs by Wr-2721. Cancer Clin Trials. 1981;4(1):3–6.

    CAS  PubMed  Google Scholar 

  26. Valeriote F, Tolen S. Protection and potentiation of nitrogen mustard cytotoxicity by WR-2721. CancerRes. 1982;42(11):4330–4331.

    CAS  Google Scholar 

  27. Jahnukainen K, Jahnukainen T, Salmi TT, Svechnikov K, Eksborg S, Soder O. Amifostine protects against early but not late toxic effects of doxorubicin in infant rats. Cancer Res. 2001;61(17):6423–6427.

    CAS  PubMed  Google Scholar 

  28. Andrieu MN, Kurtman C, Hicsonmez A, Ozbilgin K, Eser E, Erdemli E. In vivo study to evaluate the protective effects of amifostine on radiation-induced damage of testis tissue. Oncology. 2005;69(1):44–51.

    Article  PubMed  CAS  Google Scholar 

  29. Hou M, Chrysis D, Nurmio M, et al. Doxorubicin induces apoptosis in germ line stem cells in the immature rat testis and amifostine cannot protect against this cytotoxicity. Cancer Res. 2005;65(21):9999–10005.

    Article  CAS  PubMed  Google Scholar 

  30. Vendramini V, Sasso-Cerri E, Miraglia SM. Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status. Reprod Biol Endocrinol. 2010;8:3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lirdi LC, Stumpp T, Sasso-Cerri E, Miraglia SM. Amifostine protective effect on cisplatin-treated rat testis. Anat Rec (Hoboken). 2008;291(7):797–808.

    Article  CAS  Google Scholar 

  32. Yoon YD, Kim JH, Lee KH, Kim JK. Amifostine has an inhibitory effect on the radiation-induced p53-branched cascade in the immature mouse ovary. In Vivo. 2005;19(3):509–514.

    CAS  PubMed  Google Scholar 

  33. Meirow D, Lewis H, Nugent D, Epstein M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod. 1999;14(7):1903–1907.

    Article  CAS  PubMed  Google Scholar 

  34. Nagy A GM, Vintersten K, Behringer R, eds. Manipulating the mouse embryo. CSHL press. 2003;3rd ed.

  35. Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.

    Article  Google Scholar 

  36. Brady HJ, Salomons GS, Bobeldijk RC, Berns AJ. T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. EMBO J. 1996;15(6):1221–1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Familiari G, Caggiati A, Nottola SA, Ermini M, Di Benedetto MR, Motta PM. Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin’s disease. Hum Reprod. 1993;8(12):2080–2087.

    Article  CAS  PubMed  Google Scholar 

  38. Bedaiwy MA, Shahin AY, Falcone T. Reproductive organ transplantation: advances and controversies. Fertil Steril. 2008;90(6):2031–2055.

    Article  PubMed  Google Scholar 

  39. Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res. 2004;95(10):957–970.

    Article  CAS  PubMed  Google Scholar 

  40. Strauss G, Westhoff MA, Fischer-Posovszky P, et al. 4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG. Cell Death Differ. 2008;15(2):332–343.

    Article  CAS  PubMed  Google Scholar 

  41. Zhao XJ, Huang YH, Yu YC, Xin XY. GnRH antagonist cetrorelix inhibits mitochondria-dependent apoptosis triggered by chemotherapy in granulosa cells of rats. Gynecol Oncol. 2010;118(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  42. Ishida H. The research method for investigating the role of the mitochondrial permeability transition pore in cell death [in Japanese]. Nihon Yakurigaku Zasshi. 2004;123(5):329–334.

    Article  CAS  PubMed  Google Scholar 

  43. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341(pt 2):233–249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Huang YH, Zhao XJ, Zhang QH, Xin XY. The GnRH antagonist reduces chemotherapy-induced ovarian damage in rats by suppressing the apoptosis. Gynecol Oncol. 2009;112(2):409–414.

    Article  CAS  PubMed  Google Scholar 

  45. Fu X, He Y, Xie C, Liu W. Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy. 2008;10(4):353–363.

    Article  CAS  PubMed  Google Scholar 

  46. Jarrell JF, Bodo L, YoungLai EV, Barr RD, O’Connell GJ. The short-term reproductive toxicity of cyclophosphamide in the female rat. Reprod Toxicol. 1991;5(6):481–485.

    Article  CAS  PubMed  Google Scholar 

  47. Bokser L, Szende B, Schally AV. Protective effects of D-Trp6-luteinising hormone-releasing hormone microcapsules against cyclophosphamide-induced gonadotoxicity in female rats. Br J Cancer. 1990;61(6):861–865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tsai-Turton M, Luong BT, Tan Y, Luderer U. Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion. Toxicol Sci. 2007;98(1):216–230.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Reproductive Genetics, Reproductive Biomedicine Research Center, Royan Institute, ACECR, Tehran, Iran

    Zeinab Barekati MSc, Mehdi Totonchi MSc & Hamid Gourabi PhD

  2. Laboratory for Gynecological Oncology, Women’s Hospital/Department of Biomedicine, University of Basel, Switzerland

    Zeinab Barekati MSc & Ramin Radpour PhD

  3. Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute, ACECR, Tehran, Iran

    Afsaneh Golkar-Narenji MSc

Authors
  1. Zeinab Barekati MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Afsaneh Golkar-Narenji MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehdi Totonchi MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramin Radpour PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hamid Gourabi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hamid Gourabi PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barekati, Z., Golkar-Narenji, A., Totonchi, M. et al. Effects of Amifostine in Combination With Cyclophosphamide on Female Reproductive System. Reprod. Sci. 19, 539–546 (2012). https://doi.org/10.1177/1933719111426599

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719111426599

Keywords

Search

Navigation