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, weighted, 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.