Despite dramatic advances in chemotherapy, over 50% of all adults who develop acute myelogenous leukemia (AML) die with recurrent or refractory disease. Further improvements in the treatment of this disorder depend in part in understanding at a cellular level why some patients achieve sufficient tumor kill to eradicate their tumor and others receiving the same therapy do not. Recent studies suggest that several agents used to treat AML act by stabilizing a covalent adduct between the nuclear enzyme topoisomerase II (topo II) and genomic DNA, thus creating protein linked DNA strand breaks. Current therapy of newly diagnosed AML at this institution utilizes two topo II directed agents (daunorubicin and amsacrine) in combination with cytosine arabinoside. To assess the possibility that differences in topo 11 might be related to the success or failure of this therapy. A prospective study of topo II levels in clinical samples of blasts from adults with AML was undertaken. Topo II levels (assessed by Western blotting) varied at least lO fold from patient to patient. Significantly, patients whose blasts had high levels of topo II had a much lower probability of achieving complete remission. Proposed studies utilizing Northern and Southern blot analysis are designed to elucidate the mechanism of variation in copo II levels between blasts from different patients. Additional experiments will prospectively assess 1) the effect of topo II directed agents on the clonogenicity of patients' leukemic blasts in vitro, 2) the ability of topo ll directed agents to stabilize topo ll DNA adducts in intact blasts and isolated nuclei, and 3) the transport of topo II-directed agents into leukemic blasts. These studies should provide insight into the mechanisms of resistance of adult AML to topo II-directed chemotherapeutic agents and give direction to future clinical trials of methods to overcome this resistance.
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