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Modulation by CR-1409 (Lorglumide), a Cholecystokinin Receptor Antagonist, of Trypsin Inhibitor-enhanced Growth of Azaserine-induced Putative Preneoplastic Lesions in Rat Pancreas¹

Department of Gastroenterology and Hepatology, University Hospital, P. O. Box 9600, 2300 RC Leiden, The Netherlands [B. R. D., J. B. M. J. J., A. J. L. J., C. B. H. W. L.]; Department of Biological Toxicology, TNO-CIVO Toxicology and Nutrition Institute, P. O. Box 360, 3700 AJ Zeist, The Netherlands [R. A. W.]; and Rotta Research Laboratorium, Monza, Milano, Italy [L. C. R.]

Feeding of raw soya flour or other trypsin inhibitors such as camostate is a well-established method for promoting growth of (pre)neoplastic foci induced in the exocrine pancreas of rats by azaserine. The effect of trypsin inhibitors is thought to be mediated through an increased release of cholecystokinin. Using the specific cholecystokinin receptor antagonist lorglumide (CR-1409), we performed a 16-wk study to investigate the potential of this drug in inhibiting growth of putative preneoplastic foci and to determine whether and to what extent cholecystokinin is responsible for the effect of trypsin inhibitors on pancreatic growth. After initiation with 30 mg/kg of azaserine at 19 days of age, six groups of 15 rats each received one of the following treatments: camostate, cholecystokinin-8, or gelatin control, either or not in combination with CR-1409, once daily, 3 days wk for 16 wk. Plasma cholecystokinin levels, measured 30 min after the stimulus, were similar after camostate and cholecystokinin octapeptide administration. After 16 wk the pancreata were removed, weighed, and quantitatively analyzed for the number and size of putative preneoplastic foci by light microscopy. Both camostate and cholecystokinin octapeptide stimulated pancreatic growth and development of acidophilic putative preneoplastic foci, whereas growth of basophilic putative preneoplastic foci was inhibited by camostate but stimulated by cholecystokinin. CR-1409 almost completely abolished the effect of cholecystokinin and was found to cause a significant decrease in the effects of camostate. It is concluded that (a) cholecystokinin plays a significant role in camostate-stimulated growth of acidophilic putative preneoplastic foci in rat pancreas and (b) CR-1409 inhibits growth of putative preneoplastic foci induced in rat pancreas by azaserine and hence may be of potential value for the treatment of pancreatic cancer in humans.

¹ Supported by Grant IKW-86-16 from the Netherlands Cancer Foundation ("Koningin Wilhelmina Fonds").

² To whom requests for reprints should be addressed.

Received 5/18/88. Revised 11/ 2/88. Revised 1/18/89. Accepted 1/23/89.

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