Nude mice bearing xenografts of the androgen-independent human prostate-cancer cell line PC-3 were treated for 4 weeks with somatostatin analog RC-160, bombesin/gastrin-releasing peptide (GRP) antagonist (RC-3095), or the combination of both peptides. In the first experiment, treatment was started when the tumors measured approximately 10 mm3. Tumor volumes and weights were reduced by about 40% by RC-160 or RC-3095 administered by s.c. injections at doses of 100 micrograms/day/animal and 20 micrograms/day/animal respectively. The combination of RC-3095 with RC-160 did not further potentiate suppression of tumor growth, but histologically the ratio of apoptotic and mitotic indices was significantly higher in the groups treated with the combination than in the other groups. Serum gastrin levels were significantly reduced in all treated groups. Therapy with RC-160 or the combination also significantly decreased serum growth-hormone levels. Specific high-affinity binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found on the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with RC-3095, RC-160 and a combination of both analogs. Tumors from mice treated with RC-160 showed a significant increase in maximal binding capacity for somatostatin as compared with control tumors, demonstrating the absence of down-regulation. In the second experiment, treatment was started when the tumors were well developed and measured approximately 90 mm3. No significant reduction in volume, weight and growth rate of tumors was found in the groups treated with RC-160 or RC-3095. Our results suggest that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen-independent prostate cancer when the therapy is started at an early stage of tumor development.