Bombesin/gastrin releasing peptide (BN/GRP) functions as an autocrine 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 125I-GRP to SCLC cell line NCI-H345 in a dose-dependent manner and the analogue [d-Nal6, Psi13,14, Phe14] BN6–14 was approximately 6-fold more potent than was (Psi13,14, Leu14)BN with a 50% inhibition concentration value of 5 nm. [dNal6, Psi13,14, Phe14]BN6–14 and [Psi13,14, Leu14]BN and no effect on the cytosolic Ca2+ levels but antagonized the increase in cytosolic Ca2+ caused by 10 nm BN. [Psi13,14, Leu14]BN (1 µm) inhibited the growth of SCLC in vitro using a clonogenic assay by approximately 70% Also, injection of [Psi13,14, Leu14]BN (10 µg, 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.

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This research is supported in part by National Cancer Institute Grants CA-53477 and CA-48071 (T. W. M.) and CA-45153 (D. C.).

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