BOMBESIN GASTRIN-RELEASING PEPTIDE ANTAGONISTS RC-3095 AND RC-3940-IIINHIBIT TUMOR-GROWTH AND DECREASE THE LEVELS AND MESSENGER-RNA EXPRESSION OF EPIDERMAL GROWTH-FACTOR RECEPTORS IN H-69 SMALL-CELL LUNG-CARCINOMA/

BACKGROUND. Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/G RP on tumors such as small cell lung carcinoma (SCLC). Although severa l studies have addressed the intracellular events that follow the form ation of the receptor-ligand complex, the mechanism of action of BN/GR P antagonists remains unclear. METHODS. In this study the authors inve stigated the effect of synthetic BN/GRP antagonists RC-3095 and RC-394 0-II on tumor growth and the expression of epidermal growth factor rec eptors (EGF-R) in H-69 SCLC. Athymic nude mice xenografted with H-69 S CLC were treated subcutaneously for 5 weeks with RC-3095 and RC-3940-I I at the dose of 10 mu g/animal/day. RESULTS. RC-3095 decreased tumor volume by approximately 50% (P < 0.05) and RC-3940-II by 70-60% (P < 0 .01). Tumor burden also was significantly decreased in the groups trea ted with RC-3095 and RC-3940-II. Receptor analyses demonstrated high a ffinity binding sites for BN/GRP and EGF on the untreated H-69 SCLC tu mors. After treatment with RC-3095 and RC-3940-II, the concentration o f receptors for BN/GRP was decreased by 29.0% and 36.5%, respectively (both, P < 0.01) compared with controls, and EGF-R levels were reduced by 62.3% and 63.0%, respectively (both, P < 0.01). Reverse transcript ase-polymerase chain reaction and Southern blot analyses revealed that the levels of mRNA for EGF-R in tumors were lowered by 31% (P < 0.05) and 43% (P < 0.01), respectively, after treatment with RC-3095 and RC -3940-II. CONCLUSIONS. This study indicates that the inhibition of gro wth of H-69 SCLC by BN/GRP antagonists RC-3095 and RC-3940-II is accom panied by a marked decrease in the levels and mRNA expression of EGF-R . Cancer 1998;83:1335-43. (C) 1998 American Cancer Society.