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.