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Stimulation of Growth of Azaserine-induced Putative Preneoplastic Lesions in Rat Pancreas Is Mediated Specifically by Way of Cholecystokinin-A Receptors¹

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

Cholecystokinin (CCK) has been shown to stimulate the growth of both normal pancreas and azaserine-induced putative preneoplastic pancreatic lesions in the rat. The present study was performed to determine whether these effects are mediated by way of CCK-A receptors, CCK-B receptors, or both. Sixteen-day-old male Lewis rats were given i.p. injections of azaserine at 30 mg/kg body weight. Starting on day 21, rats were given s.c. injections, 5 days/week for 16 consecutive weeks, of either (a) CCK octapeptide (nonselective CCK agonist) (2.50 µg/kg body weight, n = 17), (b) tert-butyloxycarbonyl-Trp-Lys(-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH₂ (highly selective CCK-A agonist) (1.84 µg/kg body weight, n = 18), (c) [(2R,3S)-ß-MePhe²⁸,N-MeNle³¹]CCK_26–33 (highly selective CCK-B agonist) (2.40 µg/kg body weight, n = 18), or (d) normal saline solution (control, n = 17). Rats were subsequently sacrificed, pancreatic weights were determined, and quantitative morphometric analysis of atypical acinar cell foci and nodules was performed. Both CCK octapeptide and the selective CCK-A agonist tert-butyloxycarbonyl-Trp-Lys(-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH₂ stimulated pancreatic growth and the development of acidophilic atypical acinar cell foci and nodules. Furthermore, the effect produced by the selective CCK-A agonist tert-butyloxycarbonyl-Trp-Lys(-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH₂ was greater than that produced by CCK octapeptide. In contrast, the selective CCK-B agonist [(2R,3S)-ß-MePhe²⁸,N-MeNle³¹]CCK_26–33 had no effect. These findings suggest that the growth of putative preneoplastic lesions (acidophilic atypical acinar cell foci and nodules) in the rat pancreas during the early stages of azaserine-induced pancreatic carcinogenesis is mediated specifically by way of CCK-A receptors.

¹ This study was supported by a grant from the Medical Research Service of the Department of Veterans Affairs and a Cancer Research Fellowship (S. P. P.) from the Ohio Division of the American Cancer Society.

² To whom requests for reprints should be addressed, at Surgical Service (112), Department of Veterans Affairs Medical Center, 3200 Vine St., Cincinnati, OH 45220.

Received 4/ 6/93. Accepted 6/28/93.

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