Regression of nitrosamine-induced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists.
Groups of 15 female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10] LH-RH (SB-75) releasing 8 micrograms/day or with the microcapsules of the LH-RH agonist D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) releasing 8 micrograms/day or 25 micrograms/day. Chronic treatment with SB-75 resulted in 70% inhibition of pancreatic tumor weight; D-Trp-6-LH-RH in doses of 8 micrograms/day and 25 micrograms/day produced 66% and 62% inhibition, respectively. The number of animals with pancreatic tumors was reduced by about 50% in each treated group. Tumorous ascites were found in seven control hamsters and in one hamster in each group treated with D-Trp-6-LH-RH but not in the group given SB-75. Reduction in serum luteinizing hormone levels and ovarian as well as uterine weights indicated that an inhibition of the pituitary-gonadal axis occurred during chronic SB-75 and D-Trp-6-LH-RH treatment. Membrane receptor assays showed a significant decrease of the concentration of binding sites for LH-RH in tumor cells after SB-75 or D-Trp-6-LH-RH treatment. Insulin-like growth factor I receptors, but not epidermal growth factor receptors, were down-regulated by D-Trp-6-LH-RH. SB-75 did not influence the concentration or the binding capacity of insulin-like growth factor I and epidermal growth factor receptors in the tumor cells. The inhibitory effect of chronic treatment with SB-75 and D-Trp-6-LH-RH on tumor growth was mediated by enhanced apoptosis (programmed cell death) induced by the change in hormonal environment. Apoptosis was also produced in hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers by acute treatment (3 to 6 days) with high doses of D-Trp-6-LH-RH or SB-75. In view of its potency and an immediate powerful inhibitory effect, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of exocrine pancreatic cancer.
Szende
B
B
Endocrine, Polypeptide, and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana 70146.
Srkalovic
G
G
Groot
K
K
Lapis
K
K
Schally
A V
AV
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006224:Cricetinae; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008647:Mesocricetus; D009602:Nitrosamines; D010190:Pancreatic Neoplasms / Q000032:analysis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000032:analysis; D011974:Receptors, LH / Q000032:analysis; D017451:Receptors, Somatomedin; D012074:Remission Induction; D017329:Triptorelin Pamoate
D000970:Antineoplastic Agents; D009602:Nitrosamines; D011956:Receptors, Cell Surface; D011974:Receptors, LH; D017451:Receptors, Somatomedin; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; C013622:nitrosobis(2-oxopropyl)amine; C062876:cetrorelix