Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways

BACKGROUND. In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we inve stigated the effects of antagonists of growth hormone-releasing hormone (GH RH) alone or in combination with an antagonist of bombesin/gastrin-releasin g peptide (BN/GRP) on PC-3 human prostate cancers. METHODS. Nude mice implanted with PC-3 tumors received GHRH antagonists MZ- 5-156 or JV-1-38, each at 20 mu g/day s.c. In experiment 2, treatment consi sted of daily injections of JV-1-38 (20 mu g), BN/GRP antagonist RC-3940-II (10 mu g), or a combination of JV-1-38 and RC-3940-II. Serum ICE-I levels, expression of mRNA for ICE-II, and characteristics of BN/GRP and EGF recep tors in tumor tissue were investigated. RESULTS. JV-1-38 induced a greater inhibition of tumor growth and suppressi on of IGE-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum ICE-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparab le reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of ICE-II mRN A (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum ICE-I co ncentration was lowered only in mice treated with JV-1-38, while the downre gulation of BN/GRP and EGF receptors was specific for groups receiving RC-3 940-II. CONCLUSIONS. The inhibitory effects of GHRH antagonists on PC-3 human andro gen-independent prostate cancer can be potentiated by concomitant use of BN /GRP antagonists. The combination of both types of analogs apparently inter feres with both IGF and bombesin/EGF pathways, and might be clinically usef ul for the management of androgen-independent prostate cancer. Prostate 44: 172-180, 2000. (C) 2000 Wiley-Liss, Inc.