Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic cancers were treated with long-acting microcapsular preparations of the 6-D-tryptophan analog of luteinizing hormone-releasing hormone [( D-Trp6]LH-RH), releasing 25 micrograms/day; the somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160), liberating 15 micrograms/day; and the combination of these two peptides. Therapy with analogs was initiated 24 weeks after initial administration of BOP. These treatments resulted in significantly better survival of all animals as compared to BOP controls; body weights of surviving peptide-treated animals were significantly higher than those of the BOP controls. All 15 BOP-control animals had pancreatic cancers. In the group treated with RC-160 four hamsters were free of tumors, whereas therapy with [D-Trp6]LH-RH resulted in seven tumor-free animals, and combination of RC-160 and [D-Trp6]LH-RH resulted in eight tumor-free animals from groups of 15. Only preblastomatous lesions were found in these animals. Average tumor weight of animals in all peptide-treated groups, sacrificed 60 days after beginning the peptide treatment, was significantly lower than that of BOP controls. No significant differences were seen between the various peptide-treated groups. Histologically, analog-treated tumors of hamsters showed striking regressive changes characteristic of programmed cell death (apoptosis). This apoptosis presumably resulted from hormonal effects on tumor cells from prolonged treatment with these analogs of hypothalamic hormones. Our present data confirm the beneficial effect of long-acting microcapsules of [D-Trp6]LH-RH and RC-160 on pancreatic carcinoma and suggest a mode of action for these peptides. The feasibility of applying this treatment with analogs of hypothalamic hormones to human pancreatic carcinoma can be envisioned from these studies.