A neuropeptide antagonist that inhibits the growth of small cell lung cancer in vitro.
In the search for novel antiproliferative agents for small cell lung cancer (SCLC), we found the neuropeptide antagonist [Arg6, D-Trp7,9,MePhe8]substance P(6-11) to be effective in vitro. In murine Swiss 3T3 cells [Arg6,D-Trp7,9,MePhe8]substance P(6-11) was identified as a potent inhibitor of vasopressin-stimulated DNA synthesis which also blocks [3H]vasopressin binding to specific cell-surface receptors. It was a less potent antagonist of gastrin-releasing peptide and bradykinin in these cells but did not block the effects of other mitogens. In SCLC cell lines, [Arg6,D-Trp7,9,MePhe8]substance P(6-11) inhibited colony-formation in soft agarose and growth in liquid culture in a dose-dependent manner. It also blocked receptor-mediated Ca2+ mobilization induced by vasopressin, bradykinin, cholecystokinin, galanin, gastrin-releasing peptide, and neurotensin. We suggest that broad-spectrum neuropeptide antagonists can block multiple autocrine and paracrine growth loops in SCLC and could be useful therapeutic agents.
Growth Regulation Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
P J
PJ
Woll
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Rozengurt
D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004354:Drug Screening Assays, Antitumor; D019886:Gastrin-Releasing Peptide; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014667:Vasopressins / Q000037:antagonists & inhibitors / Q000494:pharmacology
D004273:DNA, Neoplasm; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D014667:Vasopressins; C046958:substance P (6-11), Arg(6)-Trp(7,9)-Me-Phe(8)-; D013373:Substance P; D019886:Gastrin-Releasing Peptide; C050702:substance P, Arg(1)-Pro(2)-Trp(7,9)-Leu(11)-; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D001920:Bradykinin; D002118:Calcium