Antagonists of bombesin/gastrin-releasing peptide as adjuncts to agonists of luteinizing hormone–releasing hormone in the treatment of experimental prostate cancer

Abstract

Palliative methods for treatment of advanced prostatic carcinoma, including those based on luteinizing hormone-releasing hormone (LH-RH) agonists, cannot prevent the ultimate growth of hormone-independent cells, and the duration of disease remission in patients with prostate cancer is limited. New therapeutic approaches combining androgen ablation therapy with other compounds must be explored. Various studies suggest that bombesin or gastrin-releasing peptide (GRP) act as autocrine growth factors and may play a role in the initiation and progression of some cancers, including those of the prostate. The effects of treatment with bombesin/gastrin-releasing peptide (GRP) receptor antagonist [D-Tpi6, Leu13 psi(CH2NH)Leu14]BN(6-14)(RC-3095), an agonist of LH-RH [D-Lys6]-LH-RH and their combination were investigated in the androgen-dependent Dunning R-3327H rat prostate cancer model. Both analogs were administered by continuous subcutaneous infusion from osmotic minipumps for 7 weeks. Tumor volumes and weights were significantly reduced by treatment with RC-3095, compared with those of controls. In rats that received [D-Lys6]-LH-RH, there was a greater decrease in tumor weight and volume than that produced by RC-3095, and the weights of testes, ventral prostate, and seminal vesicles also were reduced. The combination of RC-3095 and [D-Lys6]-LH-RH had the greatest inhibitory effect on tumor growth. Histologic parameters demonstrated a significant increase of the ratio of apoptotic to mitotic indices in the groups treated with [D-Lys6]-LH-RH or the combination. Serum LH and testosterone levels were greatly depressed by [D-Lys6]-LH-RH or the combination. Specific high-affinity binding sites for bombesin/GRP, epidermal growth factor (EGF), and insulin-like growth Factor I (IGF-I) were found on the tumor membranes. The concentration of receptors for EGF was significantly reduced by treatment with the bombesin/GRP antagonist RC-3095. Combination therapy of LH-RH analogs with bombesin antagonists such as RC-3095 might be considered for improvement of hormonal therapy of prostate cancer.