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Overexpression of Cholecystokinin Receptors in Azaserine-induced Neoplasms of the Rat Pancreas¹

Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire 03756 [R. H. B., E. T. K., D. S. L.], and Digestive Diseases Branch, NIH, Bethesda, Maryland 20892 [R. T. J.]

Cholecystokinin (CCK) is a growth factor for normal pancreas. Numerous studies also suggest that CCK promotes pancreatic carcinogenesis in the rat. Our previous studies suggested that growth of preneoplastic pancreatic foci was stimulated by CCK more than that of normal pancreas. We hypothesized that such differential growth might be due to increased numbers of CCK receptors in neoplastic tissue.

Azaserine-induced pancreatic carcinoma (DSL6) had an increased high-affinity CCK receptor binding capacity of 122 ± 23 (SD) fmol/mg protein compared to 12 ± 2 fmol/mg protein in normal pancreas (P < 0.001). The K_d of the high-affinity site was 0.33 ± 0.04 nM for carcinoma and 0.46 ± 0.08 nM for normal pancreas (P < 0.01). The amount of cholecystokinin octapeptide (CCK-8) bound to high-affinity receptor was 8.6 ± 1.9 fmol/mg protein for DSL6 compared to 0.6 ± 0.2 fmol/mg protein in normal pancreas (P < 0.001).

Azaserine-induced premalignant nodules were compared to remaining internodular pancreas. Nodules demonstrated a mean high-affinity CCK receptor binding capacity of 38 ± 9 fmol/mg protein compared to 6 ± 3 fmol/mg protein in internodular pancreas (P < 0.001). The amount of CCK-8 bound to high-affinity receptor was 3.1 ± 0.8 fmol/mg protein in nodules compared to 0.6 ± 0.3 fmol/mg protein in internodular pancreas (P < 0.001).

Overexpression of high-affinity CCK-8 receptor in premalignant and malignant azaserine-induced tumors may result in a growth advantage relative to normal pancreas.

¹ This project was supported by a grant from the Hitchcock Foundation (No. 250-94) and by NIH Grants ES-03687, CA 47327, and CA 23108, USPHS.

² Present address: Department of Surgery (ML 558), University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267.

³ To whom requests for reprints should be addressed, at Department of Pathology, Box 7600, Dartmouth Medical School, Hanover, NH 03756.

Received 9/18/91. Accepted 4/ 3/92.

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