Effect of combination treatment with analogs of luteinizing hormone-releasing hormone (LH-RH) or somatostatin and 5-fluorouracil on pancreatic cancer in hamsters.
Ductal pancreatic cancers were induced with N-nitrosobis(2-oxopropyl)amine (BOP) in female Syrian golden hamsters. The animals were then treated for 2 months with 5-fluorouracil (5-FU) and with sustained delivery systems of the LH-RH agonist D-Trp-6-LH-RH antagonist (Ac-D-Nal(2)'-D-Phe(4Cl)2-D-Pal(3)3-D-Cit6,D-Ala10)LH- RH(SB-75) and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), and with some combinations thereof. In the first experiment, the treatment with D-Trp-6-LH-RH plus 5-FU resulted in 52% inhibition of tumorous pancreas weight, a smaller number of tumor nodules on histology, a marked increase of programmed cell death (apoptosis) and a reduced number of AgNOR (argyrophilic nucleolar organizer region) in tumor cells, as compared with controls. The inhibitory effects of this combination were greater than those obtained with 5-FU and D-Trp-6-LH-RH treatment alone. In the 2nd experiment, a 76% inhibition of tumorous pancreas weight, a significant decrease in the number of tumor nodules, an increased amount of stroma, enhanced apoptosis and decreased AgNORs were observed after therapy with somatostatin analog RC-160 plus 5-FU. Most of these tumor inhibition parameters were superior to those in the group treated with 5-FU alone, and in some cases slightly better than those treated with RC-160 alone. Both LH-RH antagonist SB-75 and somatostatin analog RC-160 caused a significant inhibition of tumors, and their combination had the strongest tumor inhibitory effect, with the best survival of animals, the lowest tumorous pancreas weight and the highest apoptosis index among groups. Our results suggest that the combinations of LH-RH analogs with somatostatin analogs or of either type of analog with 5-FU may be superior to single agents in the therapy of pancreatic cancer.
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146.
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Szepeshazi
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Lapis
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Schally
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002273:Carcinogens; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives; D008647:Mesocricetus; D009602:Nitrosamines; D009929:Organ Size / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives
D002273:Carcinogens; D009602:Nitrosamines; C051458:vapreotide; D007987:Gonadotropin-Releasing Hormone; D013004:Somatostatin; C013622:nitrosobis(2-oxopropyl)amine; C034511:LHRH, pGlu(1)-Phe(2)-Trp(3,6)-; C062876:cetrorelix; D011761:Pyrrolidonecarboxylic Acid; D005472:Fluorouracil