Cytogenetic effects of amsacrine on human lymphocytes in vivo and in vitro

Amsacrine (m-AMSA) is presently being utilized in phase I-II studies at the Medicine Branch, National Cancer Institute, National Institutes of Health (Bethesda, MD), and is being administered as a continuous infusion to patients with progressive malignancy after conventional therapy. In the present study, we examined the effects of this drug, in vivo and in vitro, on chromosomal morphology and the frequency of sister chromatid exchange (SCE) induction in human peripheral blood lymphocytes. In the in vivo studies, eight patients receiving 30 mg/m2/day of m-AMSA by continuous infusion showed increased levels of chromosomal aberrations, up to a maximum of 14% (median; range, 10%-24%) at 96 hours compared to 1% (median; range, 0%-4%) in the control group; no increase was noted in SCE frequencies. In vitro studies of normal human lymphocytes with various concentrations of m-AMSA, including doses comparable to those used in vivo, showed both increased levels of chromosomal aberrations, ranging from 8% to 100%, and increased SCEs, ranging from 1.5 times the normal at the lowest concentration studied (0.005 μg/ml) to 12 times the normal (0.25 μg/ml). In correlating SCEs with breaks in the in vitro studies, it was found that two-thirds of the total breaks occurred at SCE points; this indicates a close relationship between the events leading to these two types of aberrations. In vitro isotope incorporation studies showed inhibition of both RNA and DNA synthesis but no significant inhibition of synthesis; at a dose of 5.0 μg/ml, RNA synthesis was 80% inhibited and DNA synthesis was 60% inhibited after 36 hours of incubation with m-AMSA. The difference in the results between in vitro and in vivo SCE studies may be due to possible DNA repair in the in vivo-treated lymphocytes in m-AMSA-free medium in vitro, a process not available to the in vitro-treated cells.