ANTAGONISTS OF BOMBESIN/GASTRIN-RELEASING PEPTIDE INHIBIT GROWTH OF SW-1990 HUMAN PANCREATIC ADENOCARCINOMA AND PRODUCTION OF CYCLIC-AMP

We investigated the effects of bombesin/GRP antagonists RC-3095 and RC-3940-II on the growth of SW-1990 human pancreatic adenocarcinoma cells xenografted into nude mice or cultured in vitro. Nude mice implanted with SW-1990 tumors received s.c. injections of RC-3095 and RC-3940-II or the vehicle (control) for 28 days. Chronic administration of RC-3940-II inhibited the growth of SW-1990 tumors, as shown by a reduction in tumor volume during the treatment and a significant increase in tumor doubling time. RC-3940-II decreased final tumor volume by 57.7% and tumor growth rate by 65%. Final tumor weights In mice treated with RC-3940-II were 75% lower than in controls. Treatment with RC-3095 induced smaller, and not significant, decreases in tumor volume and weight. In cell cultures, both RC-3095 and RC-3940-II effectively inhibited the proliferation of SW-1990 cells, inducing a dose- and time-dependent decrease in the number of cells. RC-3940-II again suppressed in vitro growth of SW-1990 cells more effectively than RC-3095. After 72 hr of culture, RC-3940-II and RC-3095 at 1 mu M concentrations decreased cell numbers by 45.7% and 27.7%, respectively. The estimated EC(50) value for RC-3940-II was 1 nM. When SW-1990 cells were cultured in the presence of 1 nM and 10 nM RC-3095 for 72 hr, cAMP levels in the incubation medium were decreased to 77.3% and 26.9% of the control value. Our results indicate that bombesin/GRP antagonist RC-3940-II can inhibit the proliferation of SW-1990 human pancreatic adenocarcinoma cells in vivo and in vitro. Our findings also suggest that this effect may involve the intracellular cAMP pathway. (C) 1995 Wiley-Liss, Inc.