Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis.
Imatinib mesylate (Glivec, STI 571; Novartis), a small-molecular analog of ATP that potently inhibits the tyrosine kinase activities of Bcr-Abl, PDGFR-alpha, PDGFR-beta, c-Fms, Arg and c-kit, is one of the novel molecularly targeted agents being introduced into cancer therapy. Stem cell factor (SCF)/c-kit and platelet-derived growth factor (PDGF) signaling pathways regulate postnatal formation of the pools of spermatogonial stem cells and Leydig cells in the rat testis. The effect of short postnatal imatinib exposure on fertility of the male rats and offspring of these animals were investigated. Imatinib significantly reduced the litter size sired by the treated animals and led to permanently slightly elevated serum levels of the gonadotropins. Testicular morphology and mRNA levels of ligands and receptors involved in stem cell factor/c-kit and PDGF signaling returned to control levels, and the offsprings were born healthy. Our findings indicate that treatment of cancer with certain molecularly targeted drugs may have latent effects on testicular development by inhibiting specific physiological signaling pathways.
Nurmio
Mirja
M
Department of Physiology, University of Turku, FIN-20520 Turku, Finland. mirja.nurmio@utu.fi
Kallio
Jenny
J
Toppari
Jorma
J
Jahnukainen
Kirsi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D000068877:Imatinib Mesylate; D008098:Litter Size / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010879:Piperazines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013739:Testosterone; D000068877:Imatinib Mesylate; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor