The advent of newer chemotherapeutic drugs has increased concerns about their genotoxic effects in young patients undergoing chemotherapy. Although several strategies have been proposed to conserve female fertility before and during cancer treatment, there is a lack of evidence-based data that can substantiate the efficacy and safety of these techniques. The use of chemotherapeutic medications that do not induce oocyte damage or prevent it may emerge as a new option for fertility preservation. A recent study, elucidating the pathway linked to chemotherapy-induced death of oocytes, reports the protective effect of the anticancer drug, imatinib in preserving the oocytes during such treatments. The results of the study are published online in the journal Nature Medicine.
Stefania Gonfloni from the Department of Biology, University of Rome ‘Tor Vergata’, Italy, and colleagues, conducted the study to investigate the mechanisms underlying the depletion or loss of follicular reserve with cisplatin treatment and to identify inhibitors that effectively block the associated pathway. Cisplatin and its analogs, mainly indicated for the treatment of endometrial and ovarian tumors, have been identified to play specific roles in inducing widespread chromosomal damage, as well as DNA adducts. The researchers used model human cell lines and mouse oocytes to study the activation of the c-Abl–TAp63 pathway by the chemotherapeutic DNA-damaging drug, and also analyze its role in inducing apoptosis.
The study results showed that treatment with cisplatin results in the rise of c-Abl tyrosine kinase levels. c-Abl, sensing the DNA damaging signals, in turn activates the phosporylation of TAp63. The stability of the p63 modulator protein is affected by these alterations, thereby causing a p63-dependent activation of proapoptotic promoters. Likewise, mouse oocytes treated with cisplatin contributed to the rapid accumulation of TAp63 and eventual cell death.
The study also demonstrated the efficacy of imatinib, a tyrosine kinase inhibitor, in counteracting the cisplatin-induced adverse effects, thereby suggesting the potential use of the drug in preserving the primordial follicular reserve during chemotherapy. The researchers reported that imatinib treatment inhibited cisplatin-induced effects such as the increase in c-Abl mRNA levels and the accumulation of TAp63.
Though the use of various oncotherapeutic drugs have significantly improved long-term survival and remission rates, the effect of these agents on fertility is detrimental in most cases. One of the potential strategies reported to be significant in protecting ovarian reserve in young women undergoing chemotherapy is the co-treatment with gonadotropin releasing hormone against analog (GnRHa). Earlier, Matsuo et al (The Kurume Medical Journal, 2007) concluded that GnRHa co-administration helps in reducing the gonadotoxicity linked to cisplatin treatment by desensitizing the ovary. However, a more recent review carried out by Beck-Fruchter et al (Human Reproduction Update, 2008) reported that there is a lack of substantial evidence to demonstrate the ovarian protective effect of GnRHa co-treatment with chemotherapy.
In another review, Georgescu and coworkers (Obstetrical & Gynecological Survey, 2008) analyzed the diverse options available for preserving fertility and reported the factors that should be considered for an optimal approach.
• Type of cancer
• Type of treatment adopted (chemotherapy and/or radiation)
• Patient’s age
• Time available till the initiation of treatment
• Whether the patient has a partner
Fertility preservation in cancer patients continues to be an area of huge research focus. Currently only sperm cryopreservation for men and embryo cryopreservation for women are recommended for practice, while most other alternatives such as oocyte or ovarian tissue cryopreservation are still classified as experimental.
References
1. Gonfloni S, Di Tella L, Caldarola S, et al. Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med. 2009 Oct;15(10):1179-85. Epub 2009 Sep 27.
2. Matsuo G, Ushijima K, Shinagawa A, et al. GnRH agonist acts as ovarian protection in chemotherapy induced gonadotoxicity: an experiment using a rat model. Kurume Med J. 2007;54(1-2):25-9.
3. Beck-Fruchter R, Weiss A, Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum Reprod Update. 2008 Nov-Dec;14(6):553-61.
4. Georgescu ES, Goldberg JM, du Plessis SS, Agarwal A. Present and future fertility preservation strategies for female cancer patients. Obstet Gynecol Surv. 2008 Nov;63(11):725-32.
