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 microM concentrations decreased cell numbers by 45.7% and 27.7%, respectively. The estimated EC50 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.
Qin
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Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146, USA.
Ertl
T
T
Cai
R Z
RZ
Horvàth
J E
JE
Groot
K
K
Schally
A V
AV
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis*; D019886:Gastrin-Releasing Peptide; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D010455:Peptides; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D000242:Cyclic AMP; D001839:Bombesin