Abstract
Pancreatic adenocarcinoma presents a clinical and experimental challenge because of its relative resistance to conventional modes of therapy. The present study explores a novel, biologically based approach to enhancing its chemosensitivity and to overcoming its chemoresistance in a panel of pancreatic adenocarcinoma cell lines (two human lines: PANC-1 and COLO-357; and two hamster lines: WD PaCa and PD PaCa). Difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC) that produces antiproliferative effects by polyamine depletion, was combined with the cytotoxic agent doxorubicin (DOX) in vitro. The inhibitory effects of DFMO were cytostatic and roughly additive to those of DOX. Although the response to the combination varied as a function of the cell lines studied and the response to DFMO as a single agent, all cell lines studied showed some increased inhibition with the combination. The most striking enhancement was seen in our most DOX-resistant cell line, WD PaCa, and also in PANC-1, a relatively sensitive cell line. Thus, the combination of DFMO and DOX shows promise as an experimental approach to the problem of drug resistance and the limited chemosensitivity of pancreatic cancer.
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