Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity.
Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.
Basciani
Sabrina
S
Department of Medical Physiopathology, Policlinico Umberto I, University of Rome "La Sapienza", Rome, Italy.
Brama
Marina
M
Mariani
Stefania
S
De Luca
Gabriele
G
Arizzi
Mario
M
Vesci
Loredana
L
Pisano
Claudio
C
Dolci
Susanna
S
Spera
Giovanni
G
Gnessi
Lucio
L
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007984:Leydig Cell Tumor / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D008024:Ligands; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C075278:platelet-derived growth factor A; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta