Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity

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.

Pretreatment with gonadotropin-releasing hormone antagonist protects against chemotherapy-induced testicular damage in mice

“…We have validated this method in previous studies. 21 – 23 The use of TUNEL and its range as apoptotic index is familiar to us from a number of previous studies. In our extensive experience, even with very testicular-toxic agents (e.g.…”

“… 25 It was previously shown that qPCR may serve as precise tool to measure mRNA of transcription factors that are expressed exclusively in undifferentiated spermatogonia, namely ID4 or GFRA1. 23 , 24 , 26 …”

“…In our extensive experience, even with very testicular-toxic agents (e. 25 It was previously shown that qPCR may serve as precise tool to measure mRNA of transcription factors that are expressed exclusively in undifferentiated spermatogonia, namely ID4 or GFRA1. 23,24,26 Statistical analysis Quantitative measurements are presented as mean ± standard error (SEM). Data were evaluated by independent, two-sample t-test for unequal sample sizes and unequal variances with significance of p < 0.05.…”

“…We have validated this method in previous studies. [21][22][23] The use of TUNEL and its range as apoptotic index is familiar to us from a number of previous studies. In our extensive experience, even with very testicular-toxic agents (e. 25 It was previously shown that qPCR may serve as precise tool to measure mRNA of transcription factors that are expressed exclusively in undifferentiated spermatogonia, namely ID4 or GFRA1.…”

Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

“…Among them, irinotecan has achieved the greatest success in clinical application and market due to its excellent efficacy. Irinotecan, the standard therapeutic agent of the first-line treatment for advanced or metastatic CRC, is bio-activated to 7-ethyl-10-hydroxy-camptothecin (SN38) by carboxylesterase in vivo ( Si et al, 2019 ; Levi et al, 2022 ). The main side effects of irinotecan that include diarrhea and neutropenia require dose reduction or even withdrawal ( Aiyangar et al, 2010 ; Liu et al, 2020 ).…”