Combination treatment of nitrosamine-induced pancreatic cancers in hamsters with analogs of LH-RH and a bombesin/GRP antagonist.
Analogs of luteinizing hormone-releasing hormone (LH-RH) and bombesin/gastrin-releasing peptide were previously shown to inhibit the growth of experimental pancreatic cancers. In the present study, in an attempt to increase the efficacy of therapy, female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with a combination of LH-RH agonist [D-Trp6]LH-RH or antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6-Ala10]LH-RH (SB-75) and bombesin/GRP antagonist D-Tpi6, Leu13 psi(CH2NH)Leu14bombesin(6-14) (RC-3095). The results were compared to those obtained by treatment with same doses of single peptides. LH-RH analogs and bombesin antagonist given alone significantly reduced the number of tumorous animals and decreased weight of pancreata by 46-71% and weight of tumorous pancreas by 38-64%. Histology showed lower mitotic activity and a decreased number of AgNORs in tumor cells from treated animals. Enhanced apoptosis was also observed after treatment with the LH-RH analogs. Combination therapy had no superior inhibitory effect on tumors compared to single peptides, by practically all the parameters analyzed. The reasons for this lack of potentiation are not clear. The tumor inhibitory effect of bombesin antagonists appears to be mediated by interference with EGF-receptor mechanisms. In the present study, although a significant downregulation of EGF-receptors was found in tumors treated with combination, the decrease in binding capacity for EGF was maximal in the group treated with RC-3095 alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Szepshazi
K
K
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
Halmos
G
G
Groot
K
K
Schally
A V
AV
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001839:Bombesin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008647:Mesocricetus; D009602:Nitrosamines; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D010446:Peptide Fragments / Q000008:administration & dosage*; D017329:Triptorelin Pamoate / Q000008:administration & dosage*
D009602:Nitrosamines; D010446:Peptide Fragments; D017329:Triptorelin Pamoate; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D007987:Gonadotropin-Releasing Hormone; C013622:nitrosobis(2-oxopropyl)amine; D066246:ErbB Receptors; C062876:cetrorelix; D001839:Bombesin