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Novel Expression of Gastrin (Cholecystokinin-B) Receptors in Azaserine-induced Rat Pancreatic Carcinoma: Receptor Determination and Characterization¹

Department of Surgery, University of Cincinnati College of Medicine, and Department of Veterans Affairs Medical Center, Cincinnati, Ohio 45267 [W. Z., S. P. P., R. H. B.], Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire 03756[D. S. L.]

² To whom requests for reprints should be addressed, at Department of Surgery, University of Cincinnati, College of Medicine, 231 Bethesda Ave., ML 558, Cincinnati, OH 45267-0558.

Many reports have emphasized the role of gastrin as a growth factor for normal gastrointestinal mucosa and gastrointestinal cancers. Recent studies have pointed out that this peptide acts also as a growth factor for the pancreatic cancer cell line AR42J. This effect is mediated by gastrin [cholecystokinin (CCK)-B] receptors. In the present study, we investigated gastrin (CCK-B) receptor expression in the azaserine-induced rat pancreatic carcinoma DSL-6, comparing it to normal rat pancreas, and we also characterized CCK receptor subtypes in this tumor.

The results showed that there is extensive gastrin binding to the DSL-6 pancreatic carcinoma. No evidence of specific gastrin binding to normal pancreas was found. Analysis of the ability of gastrin-17-I to inhibit ¹²⁵I-gastrin-I binding demonstrated that gastrin bound to a single class of receptors with a K_d of 0.21 ± 0.04 nM and a binding capacity of 184 ± 29 fmol/mg protein. ¹²⁵I-Gastrin-I binding was inhibited by the specific CCK-B receptor antagonist L365,260 approximately 40 times more effectively than by the specific CCK-A receptor antagonist L364,718. Analysis of the ability of cholecystokinin octapeptide (CCK-8) to inhibit ¹²⁵I-Bolton-Hunter-CCK-8 binding revealed two CCK binding sites, i.e., a high affinity site and a low affinity site. The observed binding affinities of CCK-8 were then introduced into the computer analysis of the dose-inhibition curve of the ability of gastrin-17-I to inhibit binding of ¹²⁵I-Bolton-Hunter-CCK-8, which was significantly better fit by a three-site model than by a two-site model. The three sites meet the criteria for CCK-B, high affinity CCK-A, and low affinity CCK-A receptors. The binding capacity of CCK-B receptors constitutes 34% of the total high affinity CCK binding sites.

This study demonstrated that DSL-6 pancreatic carcinoma expresses three subtypes of CCK receptors. Gastrin (CCK-B) receptors, which were not detected in normal rat pancreas, constitute about one third of the total high affinity CCK receptors. We suggest that novel expression of gastrin (CCK-B) receptors may be generated by gene mutation or amplification during carcinogenesis and may play an important role in promoting tumor growth.

¹ This study was supported by a grant from the Medical Research Service of the Department of Veterans Affairs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 1/92. Accepted 10/ 6/92.

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