Topoisomerase II Activities in Human Leukemic Cells and Their Sensitivity to Anthracyclines and Podophyllotoxines

With the purpose of defining prognostic factors for cellular response to treatment with topoisomerase II (topo II) inhibitors, we determined topo II activities in human leukemic cells and the in vitro sensitivity of these cells to topo II inhibitors. The cells from 76 patients with chronic lymphocytic leukemia (CLL, n = 28), chronic myelogonous leukemia (CML, n = 18), and acute myeloid leukemia (AML, n = 30) were examined. Fresh specimens from either peripheral blood or bone marrow were partially separated by Ficoll gradient and examined by light microscopy. Only samples with at least 80% of the cells of interest were taken into account. Either decatenation activity or relaxation activity after inhibition of topo I by camptothecin were determined in units by dilution. Under high-stringency conditions with 240 mm KGlu, two different topo II activities could be detected by their different pH optima. The activity, with its maximum at pH 8.9 (topo II α ), could be inhibited by daunorubicin, doxorubicin, idarubicin, and etoposide. In contrast, the second activity with its maximum peak at pH 7.9 (topo II β could not be inhibited. Although the topo II a activity seems to be the target substrate of these drugs, the topo II α activity is important for the sensitivity of the cells to daunorubicin and idarubicin. AML cells with a activity ratio of topo II α/β of > 1.51 were significantly more sensitive than cells with a ratio of ≤1.51 (daunorubicin P = 0.036, idarubicin P = 0.164). In CLL and CML, we found a positive correlation between the topo II β activity and the IC90 of anthracyclines and podophyllotoxines. Obviously, the topo II α activity is inhibited by these drugs, but the survival of the cells notably depends on the topo II β activity, i.e., that cells with a high topo II β activity survive the treatment.