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New Lung Cancer Drugs From Bradykinin Antagonists* FREE TO VIEW

John M. Stewart, PhD, FCCP; Lajos Gera, PhD, FCCP; Daniel C. Chan, PhD, FCCP; Eunice J. York, MS, FCCP; Laimute T. Stewart, PhD, FCCP; Vitalija Simkeviciene, PhD, FCCP; Barbara Helfrich, MS, FCCP
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*From the Departments of Biochemistry (Drs J. M. Stewart, Gera, and Simkeviciene, and Ms. York) and Medicine (Drs. Chan and L. T. Stewart and Ms. Helfrich) and the Cancer Center, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: John M. Stewart, PhD, FCCP, Professor of Biochemistry and Molecular Genetics, Box B126, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262; e-mail: john.stewart@uchsc.edu

Chest. 2004;125(5_suppl):148S. doi:10.1378/chest.125.5_suppl.148S
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Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small cell lung cancer (SCLC). These cancers have cells of neuroendocrine origin, and express receptors for a variety of neuropeptides. Bradykinin receptors are expressed on almost all lung cancer cell lines. Our very potent bradykinin antagonist B9430 (DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg) [trans-4-hydroxy-L-proline, α-2-indanylglycine, octahydroindole-2-carboxylic acid] is a candidate anti-inflammatory drug, but does not inhibit growth of SCLC. When B9430 is dimerized by N-terminal crosslinking with a suberimide linker, the product, B9870, is a potent growth inhibitor for SCLC, both in vitro and in vivo in athymic nude mice. Daily intraperitoneal injection at 5 mg/kg/d beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel “biased agonist” action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) [pentafluorocinnamic acid, O-2,6-dichlorobenzyl tyrosine, 4-amino-2,2,6,6-tetramethylpiperidine] is very potent for inhibition of SHP-77 growth in nude mice. With intraperitoneal injection at 5 mg/kg/d, M570 gave 90% suppression of tumor growth. M570 is more potent than the well-known anticancer drug cisplatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M570 also showed activity against various other cancer cell lines in vitro (SCLC, non-small cell lung cancer, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. These bradykinin antagonists in vivo also inhibit angiogenesis and matrix metalloprotease action. These compounds have clinical potential for treatment of human lung cancers.

Abbreviation: SCLC = small cell lung cancer

Supported by National Institutes of Health grants HL-26284 and CA-78154.




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