DNA but not topoisomerases is a target for a cytotoxic benzo[5,6]cyclohepta[b]indol-6-one derivative

The interaction of a newly designed benzocycloheptaindol-6-one derivative w ith DNA has been investigated by complementary spectroscopic techniques inc luding absorption, circular and lineal dichroism. Footprinting measurements were performed to delineate the sequence- selectivity of the drug-DNA inte raction and a plasmid relaxation assay was used to study the effects of the drug on human DNA topoisomerases I and II. The results clearly indicated t hat the test compound behaves as a typical DNA intercalating agent but does not stimulate DNA cleavage by topoisomerases. At the cellular level, the c ytometry measurements showed that the drug provoked a marked accumulation o f HL60 human leukemia cells in the G2/M phase of the cell cycle. DNA is thu s identified as a valid target for this new series of drugs particularly to xic to human (HL60) and murine (P388) leukemia cells.