title: Cetuximab intensifies cisplatin-induced testicular toxicity.
abstract: Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Mattan
authors.initials: M
authors.lastname: Levi
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Aron
authors.initials: A
authors.lastname: Popovtzer
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Tzabari
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Aviram
authors.initials: A
authors.lastname: Mizrachi
authors.affiliation: The Goldschleger Eye Research Institute, Sheba Medical Center, Tel Hashomer, 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors.forename: Naphtali
authors.initials: N
authors.lastname: Savion
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Shalgi
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: iritbenaharon@gmail.com.
authors.forename: Irit
authors.initials: I
authors.lastname: Ben-Aharon
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D000068818:Cetuximab / Q000008:administration & dosage / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D018675:Toxicity Tests
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D015415:Biomarkers; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D019394:Ki-67 Antigen; D054304:Anti-Mullerian Hormone; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin
keywords: cetuximab; cisplatin; epidermal growth factor receptor; testicular toxicity