Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia.

The topoisomerase (topo) Il-directed agents etoposide, daunorubicin (DNR), and amsacrine (m-AMSA) are widely used in the treatment of acute myelogenous leukemia (AML). In the present study, multiple aspects of topo Il-mediated drug action were examined in marrows from adult AML patients. Colony-forming assays revealed that the dose of etoposide, DNR, or m-AMSA required to diminish leukemic colony formation by 90% (LDso) varied over a greater than 20-fold range between different pretreatment marrows. Measurement of nuclear DNR accumulation in the absence and presence of quinidine revealed evidence of P-glycoprotein (Pgp) function in 8 of 82 samples at diagnosis and 5 of 36 samples at first relapse, but the largest quinidine-induced increment in DNR accumulation ( < 2fold) was too small to explain the variations in drug sensitivity. Restriction enzyme-based assays and sequencing of partial topo Ita and top0 118 cDNAs from the most highly resistant specimens failed to demonstrate top0 II gene mutations that could account for resistance. Western blotting of marrow samples containing greater than 80% blasts reHE NUCLEAR ENZYME topoisomerase I1 (topo 11) is a major target for a variety of antineoplastic agents, including epipodophyllotoxins, aminocridines, anthracyclines, and anthra~enediones."~ These agents allow top0 I1 to cleave DNA but slow the religation steps catalyzed by the en~yme.~ As a consequence, covalent top0 11-DNA adducts accumulate. These adducts set into motion a series of events that culminate in cell Top0 11-directed agents play a major role in the treatment of acute myelogenous leukemia (AML)."-" Induction regimens commonly contain an anthracycline or anthracenedisacrine (m-AMSA)l2.l6 or etopo~ide.~~.'~ These treatments induce complete responses in 50% to 70% of patients with newly diagnosed AML."*I The biochemical factors that determine the salutory response of some patients and not others remain largely unknown. A number of factors that affect cytotoxicity of top0 II