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Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity

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 bo...

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Autores principales: Levi, Mattan, Ben-Aharon, Irit, Shalgi, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580821/
https://www.ncbi.nlm.nih.gov/pubmed/36303648
http://dx.doi.org/10.3389/frph.2022.812053
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author Levi, Mattan
Ben-Aharon, Irit
Shalgi, Ruth
author_facet Levi, Mattan
Ben-Aharon, Irit
Shalgi, Ruth
author_sort Levi, Mattan
collection PubMed
description 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. METHODS: Mature 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). RESULTS: Females: 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. CONCLUSION: Our findings imply a mild, though irreversible effect of irinotecan on mice gonads.
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spelling pubmed-95808212022-10-26 Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity Levi, Mattan Ben-Aharon, Irit Shalgi, Ruth Front Reprod Health Reproductive Health 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. METHODS: Mature 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). RESULTS: Females: 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. CONCLUSION: Our findings imply a mild, though irreversible effect of irinotecan on mice gonads. Frontiers Media S.A. 2022-03-14 /pmc/articles/PMC9580821/ /pubmed/36303648 http://dx.doi.org/10.3389/frph.2022.812053 Text en Copyright © 2022 Levi, Ben-Aharon and Shalgi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Reproductive Health
Levi, Mattan
Ben-Aharon, Irit
Shalgi, Ruth
Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title_full Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title_fullStr Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title_full_unstemmed Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title_short Irinotecan (CPT-11) Treatment Induces Mild Gonadotoxicity
title_sort irinotecan (cpt-11) treatment induces mild gonadotoxicity
topic Reproductive Health
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580821/
https://www.ncbi.nlm.nih.gov/pubmed/36303648
http://dx.doi.org/10.3389/frph.2022.812053
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