Antagonism of Receptors for Bombesin, Gastrin and Cholecystokinin in Pancreatic Secretion and Growth

Abstract

The effects of bombesin, gastrin and cholecystokinin (CCK) on amylase secretion from the isolated rat pancreatic acini and on DNA synthesis (as biochemical indicator of trophic action) in the pancreas have been examined in 48-hour fasted and 16-hour refed rats with and without administration of specific receptor antagonists for bombesin, gastrin and CCK. Studies on the isolated rat acini revealed that bombesin, gastrin and CCK-8 all showed the same efficacy in their ability to stimulate amylase release. RC-3095, bombesin pseudopeptide antagonizing bombesin receptors, was effective only in suppressing the amylase response to bombesin but not to gastrin or CCK. Benzodiazepine receptor antagonists for gastrin (L-365,260) and for CCK (L-364,718) showed higher efficacy in the inhibition of amylase release induced by pentagastrin and CCK, respectively, but failed to affect that induced by bombesin. These peptides administered 3 times daily for 48 h in fasted rats increased the rate of DNA synthesis as measured by the incorporation of [³H]thymidine into DNA. The blockade of bombesin receptors abolished the DNA synthesis induced only by bombesin but not by gastrin or CCK. The blockade of gastrin receptors by L-365,260 suppressed the DNA synthesis induced by gastrin while the antagonism of CCK receptors by L-364,718 was effective only against CCK. Refeeding of 48-hour fasting rats strongly enhanced DNA synthesis which was significantly reduced by blocking only the CCK receptors (with L-364,718), but not the bombesin (with RC-3095) or gastrin receptors (with L-365,260). This study indicates that the secretory stimulation of pancreatic acini and DNA synthesis can be achieved by exogenous bombesin, gastrin and CCK acting via separate receptors, but that only CCK plays the major role in the postprandial stimulation of the growth of pancreatic tissue.

Inhibition of growth of PC‐82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC‐3095 or combination of agonist [D‐Trp6]‐luteinizing hormone‐releasing hormone and somatostatin analog RC‐160

“…Antagonist RC-3095 was highly active in vivo in rats, dogs, and cats in abolishing gastric and pancreatic secretion [45]. Potential oncological application of antagonist RC-3095 was revealed in our studies on pancreatic, colon, and mammary cancers, in which the administration of RC-3095 from Alzet osmotic minipumps or by daily injections powerfully inhibited the growth of these tumors [28-301. The present study provides the first evidence for the significant inhibitory effect of bombesin antagonist RC-3095 on the growth of PC-82 human prostatic cancer line xenografted in nude mice.…”

Inhibitory Effects of Antagonists of Bombesin/Gastrin Releasing Peptide (GRP) and Somatostatin Analog (RC-160) on Growth of HT-29 Human Colon Cancers in Nude Mice

“…The total binding was found to be 8.79% with 88.3% specific binding. There was 'no displacement with any of the following: insulin, Substance P, [D-Trp6] LH-RH or GRP (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). The displacement of labelled SS-14 by native SS-14 ( Fig.…”

“…These potent antagonists in nanomolar concentrations block GRP-stimulated amylase release from rat pancreatic acini, show strong binding affinity to Swiss 3T3 and H-346 SCLC cells and inhibit GRP-stimulated growth of thcsc cells in vitro (19,20). Their in vivo activity was also demonstrated in various systems (17,19).…”

“…Gastrin releasing peptide (GRP), the mammalian counterpart of the amphibian neuropeptide bombesin, is a G I hormone, stimulating gastrointestinal enteropancreatic hormone release and pancreatic and intestinal epithelial growth (10,12,17). Specific GRP receptors are found throughout the mammalian G I tract.…”

Different actions of CCK on pancreatic and gastric growth in the rat: effect of CCKA receptor blockade

“…In addition, Göke et al , (1986) showed that chronic stimulation of endogenous CCK release by camostate also induces pancreatic hypertrophy and hyperplasia. Subsequent studies (Niederau et al , 1986; Wisner et al , 1988; Schmidt et al , 1989; Douglas et al , 1990; Konturek et al , 1991) have confirmed the initial observation and have shown that this effect is mediated through stimulation of CCK A ‐receptors.…”