Several
bombesin-receptor antagonists are available that inhibit secretory and growth effects of
bombesin, in vitro. In the present study, we examined the effects of a new class of
bombesin receptor antagonists (modified GRP(15-27)
peptides, with D-Pro26 and D-Ala24 moieties), on
bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested,
BW-10 or
2258U89 ([de-NH2)Phe19,D-Ala24,D-Pro26 psi(CH2NH)Phe27]-GRP(19-27)) was most potent towards inhibiting
bombesin binding to rat pancreatic acinar
cancer cells with an ID50 of 0.5 nM.
BW-10 (1 and 10 nM) significantly inhibited the
gastrin response to 1 nM
bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion.
BW-10 (10-100 nmol/kg) was equally effective at significantly inhibiting
bombesin evoked
gastrin release in anesthetized rats, in vivo. [D-Phe6]
Bombesin(6-13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced
bombesin provoked
gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective.
Intravenous infusion of
BW-10 (10 nmol/kg/h) partially depressed
gastrin and
pancreatic polypeptide and completely abolished
insulin released in response to
bombesin, in conscious dogs. These results suggest that
BW-10 functions as one of the most potent
bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.