bombesin--leu(13)-psi-ch2nh-leu(14)- and Lung-Neoplasms

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 had no effect on the cytosolic Ca2+ levels but antagonized the increase in cytosolic Ca2+ caused by 10 nM BN. [Psi13,14, Leu14]BN (1 microM) inhibited the growth of SCLC in vitro using a clonogenic assay by approximately 70% Also, injection of [Psi13,14, Leu14]BN (10 micrograms, 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.

Topics: Animals; Bombesin; Calcium; Carcinoma, Small Cell; Dose-Response Relationship, Drug; Female; Gastrin-Releasing Peptide; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Peptides; Receptors, Bombesin; Receptors, Neurotransmitter; Signal Transduction; Tumor Cells, Cultured; Tumor Stem Cell Assay