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[D-Arg¹,D-Trp^5,7,9,Leu¹¹]Substance P: A Novel Potent Inhibitor of Signal Transduction and Growth in Vitro and in Vivo in Small Cell Lung Cancer Cells

Imperial Cancer Research Fund, P.O. Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom [M. J. S., T. H., E. R.]; Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, United Kingdom [M. J. S.]; and Peptech, 4–10 Inman Road, P.O. Box 444, Dee Why, New South Wales 2099, Australia [F. W.]

[D-Arg¹,D-Trp^5,7,9,Leu¹¹]Substance P (SP) was identified out of a panel of novel SP analogues as the most potent inhibitor of small cell lung cancer (SCLC) cell growth. This analogue inhibited proliferation of H-510 and H-69 SCLC cells in liquid culture and in semisolid media (IC₅₀, 5 µM). Colony formation stimulated by multiple neuropeptides, including vasopressin and bradykinin, was also blocked by [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP. This new SP analogue inhibited vasopressin- or bradykinin-induced Ca²⁺ mobilization and mitogen-activated protein kinase activation. Administration of [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP inhibited the growth of an H-69 xenograft in nude mice. Our results support the hypothesis that SP analogue broad-spectrum neuropeptide antagonists could be of therapeutic value in SCLC.

¹ To whom requests for reprints should be addressed. Phone: 44-171-269-3455; Fax: 44-171-269-3417.

Received 10/15/96. Accepted 11/15/96.

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