Growth hormone-releasing hormone (GHRH) antagonists inhibit the proliferation of androgen-dependent and -independent prostate cancers.
The antiproliferative effects of an antagonist of growth hormone-releasing hormone (GHRH) JV-1-38 were evaluated in nude mice bearing s.c. xenografts of LNCaP and MDA-PCa-2b human androgen-sensitive and DU-145 androgen-independent prostate cancers. In the androgen-sensitive models, JV-1-38 greatly potentiated the antitumor effect of androgen deprivation induced by surgical castration, but was ineffective when given alone. Thus, in castrated animals bearing MDA-PCa-2b cancers, the administration of JV-1-38 for 35 days virtually arrested tumor growth (94% inhibition vs. intact control, P < 0.01; and 75% vs. castrated control, P < 0.05). The growth of LNCaP tumors was also powerfully suppressed by JV-1-38 combined with castration (83% inhibition vs. intact control, P < 0.01; and 68% vs. castrated control, P < 0.05). However, in androgen-independent DU-145 cancers, JV-1-38 alone could inhibit tumor growth by 57% (P < 0.05) after 45 days. In animals bearing MDA-PCa-2b and LNCaP tumors, the reduction in serum prostate-specific antigen levels, after therapy with JV-1-38, paralleled the decrease in tumor volume. Inhibition of MDA-PCa-2b and DU-145 cancers was associated with the reduction in the expression of mRNA and protein levels of vascular endothelial growth factor. The mRNA expression for GHRH receptor splice variants was found in all these models of prostate cancer. Our results demonstrate that GHRH antagonists inhibit androgen-independent prostate cancers and, after combination with androgen deprivation, also androgen-sensitive tumors. Thus, the therapy with GHRH antagonist could be considered for the management of both androgen-dependent or -independent prostate cancers.
Letsch
Markus
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Schally
Andrew V
AV
Busto
Rebeca
R
Bajo
Ana M
AM
Varga
Jozsef L
JL
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000097:blood / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A
D016228:Endothelial Growth Factors; C411623:JV 1-38; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013007:Growth Hormone-Releasing Hormone; D017430:Prostate-Specific Antigen