Loss of viability and induction of DNA damage in human leukemic myeloblasts and lymphocytes by m-AMSA

The effects of m-AMSA on in vitro viability and on the induction of DNA damage were examined in low-growth-fraction cell populations of human leukemic myeloblasts and normal lymphocytes. A significant individual variation in the drug-induced reduction of in vitro viability was observed in studies with five selected leukemic patients. The concentration of m-AMSA required to reduce viability by 50% within 48 h ranged from 0.25 μM to in excess of 5.0 μM for the leukemic myeloblasts as against about 2.0 μM for the samples of normal lymphocytes. Alkaline elution studies showed that m-AMSA induced protein-associated DNA strand breaks (PADB) in both myeloblasts and lymphocytes. Depending upon the m-AMSA concentration, there was a 4- to 9-fold difference in the level of PADBs induced by a given drug concentration in the myeloblasts of eight patients studied. The level of PADBs was saturable with respect to both drug concentration (5–10 μM) and exposure time (45–10 μM). The PADBs were repaired rapidly in all the lymphocyte and myeloblast samples studied, with over 90% of this DNA damage being repaired within 45 min after resuspension of the cells in drug-free medium. These studies of m-AMSA in low-growth-fraction samples of human lymphocytes and myeloblasts show both similarities and differences in the action of this drug compared with previously published studies using the high-growth-fraction mouse L1210 system.