[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a potent bombesin antagonist in murine Swiss 3T3 cells, inhibits the growth of human small cell lung cancer cells in vitro.
In the search for a more potent bombesin antagonist, we found [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P to be effective in mouse fibroblasts and to inhibit the growth of small cell lung cancer, a tumor that secretes bombesin-like peptides that may act as autocrine growth factors. In murine Swiss 3T3 cells, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P proved to be a bombesin antagonist as judged by the following criteria: (i) inhibition of DNA synthesis induced by gastrin-releasing peptide and other bombesin-like peptides; (ii) inhibition of 125I-labeled gastrin-releasing peptide binding to the bombesin/gastrin-releasing peptide receptor; (iii) reduction in cross-linking of the Mr 75,000-85,000 protein putatively a component of the bombesin/gastrin-releasing peptide receptor; (iv) blocking of early cellular events that precede mitogenesis--calcium mobilization and inhibition of epidermal growth factor binding. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P was 5-fold more potent than the antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]substance P. [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P also inhibits mitogenesis induced by vasopressin but not that induced by a variety of other mitogens. Both antagonists reversibly inhibited the growth of small cell lung cancer in vitro in a concentration-dependent manner. Peptide antagonists could, therefore, have far-reaching therapeutic implications.
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000037:antagonists & inhibitors*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D004261:DNA Replication / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D019886:Gastrin-Releasing Peptide; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008970:Molecular Weight; D010455:Peptides / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D010455:Peptides; D013373:Substance P; D004815:Epidermal Growth Factor; D019886:Gastrin-Releasing Peptide; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D001839:Bombesin