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 investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin- releasing 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 μg/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 μg), BN/GRP antagonist RC-3940-II (10 μg), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated. RESULTS. JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable 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 IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940- II (77%). Serum IGF-I concentration was lowered only in mice treated with JV- 1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II. CONCLUSIONS. The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen- independent prostate cancer. (C) 2000 Wiley-Liss, Inc.