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[Psi^13,14] Bombesin Analogues Inhibit Growth of Small Cell Lung Cancer in Vitro and in Vivo¹

Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037 [S. M., J. S., T. W. M.]; Biomeasure Incorporated, Hopkinton, Massachusetts 01748 [J. T., A. B., J-P. M.]; Tulane University School of Medicine, New Orleans, Louisiana 70112 [D. C.]; NCI-Navy Medical Oncology Branch, National Cancer Institute and Naval Hospital, Bethesda, Maryland 20814 [I. A., F. C., J. L. M.]

Bombesin/gastrin releasing peptide (BN/GRP) functions as an autocrine growth factor in small cell lung cancer (SCLC). Previously, this autocrine growth cycle was disrupted by a monoclonal antibody which binds to the carboxyl terminal of BN and neutralizes the peptide so that it is unable to interact with the BN/GRP receptor. Here a series of BN analogues were synthesized which have a reduced peptide bond near the carboxyl terminal. The analogues inhibited specific binding of ¹²⁵I-GRP to SCLC cell line NCI-H345 in a dose-dependent manner and the analogue [D-Nal⁶, Psi^13,14, Phe¹⁴] BN^6–14 was approximately 6-fold more potent than was (Psi^13,14, Leu¹⁴)BN with a 50% inhibition concentration value of 5 nM. [DNal⁶, Psi^13,14, Phe¹⁴]BN^6–14 and [Psi^13,14, Leu¹⁴]BN and no effect on the cytosolic Ca²⁺ levels but antagonized the increase in cytosolic Ca²⁺ caused by 10 nM BN. [Psi^13,14, Leu¹⁴]BN (1 µM) inhibited the growth of SCLC in vitro using a clonogenic assay by approximately 70% Also, injection of [Psi^13,14, Leu¹⁴]BN (10 µg, s.c.) inhibited the growth of SCLC xenografts in nude mice in vivo by approximately 50%. These data suggest that the autocrine growth cycle of BN/GRP in SCLC may also be disrupted by peptide antagonists which bind to the BN receptor.

¹ This research is supported in part by National Cancer Institute Grants CA-53477 and CA-48071 (T. W. M.) and CA-45153 (D. C.).

² To whom requests for reprints should be addressed.

Received 11/29/89. Accepted 1/24/91.

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