Inhibitory effect of bombesin/gastrin-releasing peptide antagonist RC-3095 and high dose of somatostatin analogue RC-160 on nitrosamine-induced pancreatic cancers in hamsters.
Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 months with new pseudononapeptide bombesin receptor antagonist [D-Tpi6,Leu13 psi (CH2NH)-Leu14]bombesin(6-14)(RC-3095), administered s.c. with implanted osmotic minipumps releasing 20 micrograms/day of the analogue. The results were compared to those obtained by treatment with somatostatin analogue RC-160 (35 micrograms/day and 150 micrograms/day) or [D-Trp6]luteinizing hormone-releasing hormone (25 micrograms/day), which inhibited the growth of pancreatic cancers in our previous studies. A new acetylated somatostatin analogue [formula: see text] (30 micrograms/day) also was used for comparison of therapeutic response. All peptide analogues induced tumor inhibition by at least one of the measured parameters. Bombesin antagonist RC-3095 and high dose of RC-160 (150 micrograms/day) had the greatest inhibitory effect on pancreatic cancers: A significant decrease in the number of animals with tumors, reduced pancreatic weight, 87-89% inhibition of tumorous pancreas weight, and a significant diminution in the number of tumor nodules and argyrophilic nucleolar organizer region count in tumor cell nuclei were observed in the groups treated with these regimens. We were able to detect receptors for bombesin in membranes of N-nitrosobis(2-oxopropyl)amine-induced pancreatic tumors and these receptors were not down-regulated after treatment with the bombesin antagonist. In hamsters treated with bombesin antagonists, tumor inhibition might be explained by a significant decrease in the binding capacity of epidermal growth factor receptors in pancreatic cancers. The acetylated somatostatin analogue RC-160-II had a similar inhibitory effect on the tumors as the original analogue RC-160. Our results suggest that the increase in the dose of RC-160 improves the therapeutic response, and this finding should be taken into account in clinical use of this somatostatin analogue. In view of its strong inhibitory effect on experimental pancreatic tumors, the bombesin antagonist RC-3095 might be considered as a possible new agent for the therapy of human exocrine pancreatic cancer.
Szepeshazi
K
K
Department of Medicine, Tulane University Medical School, New Orleans, Louisiana 70112.
Schally
A V
AV
Cai
R Z
RZ
Radulovic
S
S
Milovanovic
S
S
Szoke
B
B
D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002273:Carcinogens; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005755:Gastrins / Q000097:blood; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009602:Nitrosamines; D009929:Organ Size / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002273:Carcinogens; D005755:Gastrins; D009602:Nitrosamines; D010446:Peptide Fragments; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; C051458:vapreotide; D013004:Somatostatin; C013622:nitrosobis(2-oxopropyl)amine; D066246:ErbB Receptors; D001839:Bombesin