The overall goal of this project is to improve the treatment of patients with high-risk acute non-lymphocytic leukemia by developing mechanism-based topoisomerase-targeting therapies. The recent development of topotecan as a topoisomerase I-targeting drug that is active in the therapy of leukemia allows investigation of rationally designed combination regimens involving both topoisomerase I- and topoisomerase Il-targeting drugs. Cell culture models indicate that resistance to topotecan often involves drug efflux, or downregulation or mutation of topoisomerase I. New data also implicate ubiquitin/proteasome pathways in resistance to camptothecins. Moreover, cellular resistance to camptothecins is usually accompanied by upregulation of topoisomerase II protein levels and catalytic activity, resulting in hypersensitivity to topoisomerase Il-targeting drugs such as etoposide. Initial studies involving cells obtained from patients treated with topotecan suggest that these preclinical models may be clinically relevant. However, relatively little is known regarding treatment-induced alterations in cellular topoisomerase levels and activity in patients with leukemia, and the mechanisms of resistance to topotecan that are operative in these patients are unknown. ? ? In the first aim of this project, topoisomerase Il protein levels and activity will be quantified in blasts obtained from patients receiving cytosine arabinoside/topotecan induction therapy. The timing of peak topoisomerase Il alterations will be evaluated to determine an optimal time for administration of etoposide. Subsequently, the maximum-tolerated dose of etoposide will be identified for this schedule of drug administration. ? ? The second aim concerns identification of clinical mechanisms of resistance to topotecan, and includes analyses of intracellular topotecan accumulation, BCRP expression, topoisomerase I mutations, and topoisomerase I ubiquitylation and degradation in blasts obtained from patients. The data obtained from the first and second aims will be correlated with clinical outcomes in the third aim. The results of these studies should provide insight into clinical mechanisms of resistance to topotecan, and allow rational development of a topoisomerase-targeting strategy in the treatment of leukemia.
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