This project involves a study of the modes of resistance of tumor cells to anthracyclines and other selected natural products. The goal is the delineation of determinants of drug responsiveness in human neoplasia, since a more detailed understanding of resistance phenomena could lead to improved therapeutic design. In many tumor cell types, of both human and animal origin, there is evidence for a broad-spectrum (pleiotropic) cross-resistance pattern involving anthracyclines, vinca alkaloids, AMSA and other natural and synthetic products. We plan to examine the some of the mechanisms which underlie pleiotropic resistance, and to determine whether this phenomenon is relevant at levels of drug resistance encountered in the clinic, or at levels of drug resistance attained only in cell culture or via chronic drug therapy of tumor-bearing animals over many transplant generations. Several model systems will be utilized, including murine ascitic tumors varying in anthracycline responsiveness, solid murine tumors, freshly-isolated myeloblasts from patients with acute leukemias, biopsy samples from patients with breast cancer, and human-derived small-cell and ovarian carcinoma in cell culture. Among the resistance modes to be examined are those relating to drug transport, intracellular binding, SH-mediated drug detoxification and enhanced repair of drug-induced damage. Experiments will be carried out to evaluate each mode of resistance in the different tumor systems, and the effectiveness of different procedures for circumvention of such resistance.
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