Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various cancers and affect tumoral growth factors.METHODS.
We investigated the effect of a new GHRH antagonist MZ-J-7-138 at doses of 1.25, 2.5, 5 and 10 μg/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 μg/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 μg/day. The suppression of IGF-II protein levels in tumors was seen at all doses of MZ-J-7-138, but only 10 μg dose induced a significant inhibition. MZ-J-7-138 also reduced VEGF protein levels, the inhibition being significant at doses of 5 and 10 μg. Specific high affinity binding sites for GHRH were found on PC-3 tumors using 125I-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.