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Antiproliferative Effects of Gastrin Receptor Antagonists and Antibodies to Gastrin on Human Colon Carcinoma Cell Lines¹

Bristol-Baylor Laboratory, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [N. M. H., D. K. M., M. G. B.]; Pharmaceutical Research and Development Division, Bristol-Myers Company, Wallingford, Connecticut 06492 [P. A. K., R. C. C., M. G. B.]; and Rotta Research Laboratorium, 20050 S. Fruttuoso Monza, Milano, Italy [L. C. R.]

The gastrointestinal hormone gastrin has been shown to stimulate the growth of normal colonic mucosa. To examine for a possible role of gastrin in the proliferation of cultured colon tumor cells, we have studied the effects of two gastrin receptor antagonists, proglumide and benzotript, and of antibodies to gastrin. We find that proglumide (50% effective concentration, 2 to 5 mM) and benzotript (50% effective concentration, 0.4 to 0.8 mM) inhibit the monolayer growth of six human colon cancer cell lines. Addition of exogenous gastrin abrogated the growth-inhibitory effect of proglumide. The anchorage-independent growth of colon carcinoma cells was also inhibited by the two gastrin antagonists. Also, a dose-dependent increase in carcinoembryonic antigen secretion was observed upon treatment with proglumide and benzotript in three cell lines examined. Half-maximal inhibition of labeled gastrin binding was observed at concentrations of 0.4 mM benzotript and 8.6 mM proglumide. In addition, antigastrin antiserum added to HCT 116 cells adapted to growth in serum-free medium resulted in a concentration-dependent inhibition of cellular proliferation. These data suggest that gastrin may function as an autocrine growth factor in colon carcinoma.

¹ Supported by NIH Grants CA34432 and CA45967.

Received 5/11/88. Revised 8/29/88. Accepted 9/ 8/88.