Delay in diagnosis and relative refractoriness of available therapeutic modalities are largely responsible for the dismal prognosis of patients with adenocarcinoma of the pancreas, a cancer which appears to be increasing in incidence. Innovative, experimental approaches to therapy as well as a better understanding of the relative chemoresistance of pancreatic adenocarcinoma are needed. The present proposal would continue our on-going program of testing experimental agents against a panel of tumor models in the search for drugs active against pancreatic cancer. We will also continue to maintain and expand our existing panel of tumor models in the athymic (nude) mouse and tissue culture. Our preliminary data suggest that cellular levels of ornithine decarboxylase (ODC), a growth regulating enzyme that is characteristically elevated in malignantly-transformed cells, may correlate with phenotypic differences in the pancreatic cancer cell lines in terms of degree of differentiation and resistance to cytotoxic agents. Thus, the following hypotheses will be investigated: a) that drug resistance is associated with elevated ODC activity and/or half-life, and b) that inhibition of ODC by means of the irreversible inhibitor D, L-alpha-difluoromethyl ornithine (DFMO) may be a means of overcoming drug resistance. The investigations will be carried out in tissue culture using 2 hamster and 2 human cell lines of pancreatic adenocarcinoma and in vivo using the 2 hamster tumor models and 2 human xenografts in nude mice. Colony formation assays will be used to assess the reproductive capacity of the cell lines in response to cytotoxic agents alone and in combination with DFMO. Other parameters to be studied include cell kinetics, ODC activity and half-life, and drug uptake. Investigations to assess the interaction of ODC, DFMO, and cytotoxic chemotherapy will be conducted first in vitro to determine optimal dose/scheduling relationships, followed by in vivo studies. An increase in the therapeutic index is anticipated by combining DFMO with cytotoxic agents, since DFMO has relatively low toxicity. The long-term objective of the project is to provide information that can be used to design more rational and effective chemotherapy trials for pancreatic cancer to provide a basis for the understanding of the sensitivity and/or resistance of pancreatic cancer to chemotherapy.