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Bradykinin Antagonist Dimer, CU201, Inhibits the Growth of Human Lung Cancer Cell Lines in Vitro and in Vivo and Produces Synergistic Growth Inhibition in Combination with Other Antitumor Agents¹

Lung Cancer Program of the University of Colorado Cancer Center [D. C. ., L. G., J. M. S., B. H., T. L. Z., P. A. B.] and the Departments of Medicine [D. C. C., B. H., T. L. Z., P. A. B.] and Biochemistry [L. G., J. M. S.], University of Colorado Health Sciences Center, Denver, Colorado 80262; College of Pharmacy, Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210 [W. Y. F., K. K. C.]; the National Cancer Institute, Bethesda, Maryland 20892 [J. M. C.]; and Carcinex Inc., Boulder, Colorado 80301 [D. C., L. G., J. M. S., P. A. B.]

Small cell lung cancers (SCLCs), many non-SCLCs, andother cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel bradykinin antagonist dimer, CU201 (B9870), that acts as a "biased agonist" for neuropeptides by blocking G_q signaling and activating G_12,13 signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c_max was 5773 ng/ml (5 µM), and the decay was biexponential. When fitted to a two-compartment model, the t_1/2 was 14.4 min, and the t_1/2ß was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.

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