Dose-Dependent Growth Inhibition In Vivo of PC-3 Prostate Cancer With a Reduction in Tumoral Growth Factors After Therapy With GHRH Antagonist MZ-J-7-138

BACKGROUND. Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various cancers and affect tumoral growth factors. METHODS. We investigated the effect of anew GHRH antagonist MZ-J-7-138 at doses of 1.25, 2.5, 5 and 10 mu g/day s.c. on the growth of PC-3 human androgen independent prostate cancers xenografted s.c. into nude mice. Binding assays were used to investigate GHRH receptors. The levels of IGF-II and VEGF in tumors were measured by radioimmunoassays. RESULTS. Treatment with 2.5, 5, and 10 mu g/day MZ-J-7-138 caused a significant dose-dependent growth reduction of PC-3 tumors. The greatest inhibition of 78% was obtained with 10 mu g/day. The suppression of IGF-II protein levels in tumors was seen at all doses of MZ-J-7-138, but only 10 mu g dose induced a significant inhibition. MZ-J-7-138 also reduced VEGF protein levels, the inhibition being significant at doses of 5 and 10 mu g. Specific high affinity binding sites for GHRH were found on PC-3 tumors using I-125-labeled GHRH antagonist JV-1-42. MZ-J-7-138 displaced radiolabeled JV-1-42 with an IC50 of 0.32 nM indicating its high affinity to GHRH receptors. Real-time PCR analyses detected splice variant 1 (SV1) of GHRH receptor (GHRH-R) as well as pituitary type of GHRH-R and GHRH ligand. CONCLUSION. Our results demonstrate the efficacy of GHRH antagonist MZ-J-7-138 in suppressing growth of PC-3 prostate cancer at doses lower than previous antagonists. The reduction of levels of growth factors such as VEGF and IGF-II in tumors by GHRH antagonist was correlated with the suppression of tumor growth. Prostate 68: 1763-1772, 2008. (C) 2008 Wiley-Liss, Inc.