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 µg/day or with the microcapsules of the LH-RH agonist d-tryptophan-6-luteinizing hormone-releasing hormone (d-Trp-6-LH-RH) releasing 8 µg/day or 25 µg/day. Chronic treatment with SB-75 resulted in 70% inhibition of pancreatic tumor weight; d-Trp-6-LH-RH in doses of 8 µg/day and 25 µg/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.

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This work was supported by NIH Grant CA 40077, the Medical Research Services of the Veterans Administration, and the G. Harold and Leila Y. Mathers Foundation, all to A. V. S.

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