Bombesin Analogues Inhibit Growth of Small Cell Lung Cancer in Vitro and in Vivo1

Bombesin/gastrin releasing peptide (BN/GRP) functions as an auto crine growth factor in small cell lung cancer (SCLC). Previously, this autocrine growth cycle was disrupted by a monoclonal antibody which binds to the carboxyl terminal of BN and neutralizes the peptide so that it is unable to interact with the BN/GRP receptor. Here a series of BN analogues were synthesized which have a reduced peptide bond near the carboxyl terminal. The analogues inhibited specific binding of I2SI-GRP to SCLC cell line NCI-H345 in a dose-dependent manner and the analogue [D-Nal6, Psi13-14, Phe'4| BN6"14was approximately 6-fold more potent than was (Psi13-14, Leu'4)BN with a 50% inhibition concentration value of 5 nivi. |oNal«,Psi'3-14,Phe'4]BN6-'4 and |Psi13-14,Leu'4|BN had no effect on the cytosolic Ca2* levels but antagonized the increase in cytosolic Ca2+caused by 10 niviBN. |Psi13-14, Leu'4]BN (1 MM)inhibited the growth of SCLC in vitro using a clonogenic assay by approximately 70% Also, injection of [Psi13-14,Leu14]BN (10 fig, s.c.) inhibited the growth of SCLC xenografts in nude mice in vivo by approximately 50%. These data suggest that the autocrine growth cycle of BN/GRP in SCLC may also be disrupted by peptide antagonists which bind to the BN receptor.