Abstract
Background:Gonadal toxicity following chemotherapy is an important issue among the population of young cancer survivors. The inhibitor of DNA topoisomerase I, irinotecan (CPT-11), is widely used for several cancer types. However, little is known about the effect of irinotecan on the fertility of both genders. Thus, the aim of the present study was to evaluate irinotecan gonadotoxicity, using a mouse model.MethodsMature male and female mice were injected intraperitoneally with either saline (), irinotecan (100 mg/kg) or cyclophosphamide (100 mg/kg); and sacrificed one week or three months later for an acute or long-term toxicity assessment, respectively. We used thorough and advanced fertility assessment by already established methods: Gonadal and epididymal weights, as well as sperm count and sperm motility were determined; serum anti-Müllerian hormone (AMH) was measured by ELISA. Immunohistochemistry (Ki-67), immunofluorescence (PCNA, CD34), terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labeling (TUNEL) and computerized analysis were performed to examine gonadal proliferation, apoptosis and vascularization. qPCR was used to assess the amount of testicular spermatogonia (Id4 and Gafra1 mRNA) and ovarian primordial oocytes reserves (Sohlh2, Nobox and Figla mRNA).ResultsFemales: Irinotecan administration induced acute ovarian apoptosis and decreased vascularity, as well as a mild, statistically significant, long-term decrease in the number of growing follicles, ovarian weight, and ovarian reserve. Males: Irinotecan administration caused an acute testicular apoptosis and reduced testicular spermatogenesis, but had no effect on vascularity. Irinotecan induced long-term decrease of testicular weight, sperm count and testicular spermatogonia and caused elevated serum AMH.ConclusionOur findings imply a mild, though irreversible effect of irinotecan on mice gonads.
Highlights
Irinotecan (7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; CPT-11), alone or in combination with other drugs, has been used clinically, showing high response rates in the setting of uterine cancer, ovarian cancer, lung cancer, gastric cancer and malignant lymphoma [1]
We examined the effect of irinotecan on mouse gonads, 1 week or 3 months after drug administration, for assessment of gonadal short- and long-term effects, respectively
We examined the effect on several conventional markers of ovarian function and on ovarian reserve, which are known to be affected by chemotherapy insult
Summary
Irinotecan (7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin; CPT-11), alone or in combination with other drugs, has been used clinically, showing high response rates in the setting of uterine cancer, ovarian cancer, lung cancer, gastric cancer and malignant lymphoma [1]. Irinotecan and its more active derivative, SN-38, is a powerful S phase-specific inhibitor of DNA topoisomerase I, a key nuclear enzyme for the relaxation of DNA double helix super-coiling during replication. Irinotecan shows strong clinical antitumor effects by antagonizing DNA synthesis and is used widely for cancer treatment, metastatic colorectal cancer, and for the treatment of solid tumors [3]. Bone marrow suppression, such as neutropenia and thrombocytopenia, are well known as frequent severe adverse effects of irinotecan. The inhibitor of DNA topoisomerase I, irinotecan (CPT-11), is widely used for several cancer types. The aim of the present study was to evaluate irinotecan gonadotoxicity, using a mouse model
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