DNA TOPOISOMERASE ACTIVITY AND CANCER THERAPY

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Numerous antineoplastic agents, including intercalators and epipodophyllotoxins, exert their cytotoxic effect via inhibition of the nuclear enzyme, DNA topoisomerase II. Studies of drug-resistant cell lines by several investigators have helped define mechanisms of resistance to topoisomerase II-active drugs. Both a decrease in the target enzyme (topoisomerase II) which occurs when cells progress to quiescence, as well as alterations in the enzyme itself which result in drug insensitivity, have been shown to result in resistance. A role for altered modulation of topoisomerase II activity in drug resistance has also been suggested. The following studies are likely to further define mechanisms of resistance to topoisomerase II inhibitors. The multiple drug resistance of the Chinese hamster ovary (CHO) TAM-16C2 cell fine appears to reside in, as yet, poorly defined nuclear factors. This cell line may have an alteration in the control of topoisomerase II activity, and elucidation of these nuclear factors will help define "normal" enzyme control as well as the resistance of these cells. Three other drug-resistant CHO cell lines, similar to TAM-16C2 cells in that they were selected in the presence of VP-l6, will also be evaluated for their mechanisms of resistance. A paucity of information concerning the basis for mitoxantrone resistance exists. CHO cell lines made resistant to this new antitumor agent, will be isolated and characterized in an effort to define the possible role of perturbations of topoisomerase II in resistance to mitoxantrone. In addition to these studies on drug resistance, the response of multiple myeloma cells to topoisomerase II inhibitors will be investigated at several levels. The drug resistance of RPMI 8226 DOX 1 V human myeloma cells will be evaluated; resistance appears to result from diminished topoisomerase II activity. That topoisomerase II is the target of several antitumor drugs and that cytotoxicity correlates with the content of target enzyme, suggests that IL-6-stimulated human myeloma ILKM3 cells will be hypersensitive to the cytotoxic effects of VP-16 if the increased proliferation augments topoisomerase II. This same approach will be used in an attempt to purge myeloma cells from the bone marrow of patients with this disease. In short, the research described herein endeavors to elucidate mechanisms of resistance to topoisomerase II inhibitors and to apply recent observations regarding cytotoxicity mediated by this enzyme in a clinical paradigm.