Advances in Brief W-S-DiacetoxypentyOdoxorubicin: A Novel Anthracycline Producing DNA Interstrand Cross-Linking and Rapid Endonucleolytic Cleavage in Human Leukemia Cells

The cytotoxic and DNA-damaging effects of a novel alkylating anthracycline, yV-(5,5-diacetoxypentyl)doxorubicin, were quantified in HL-60 human leukemia cells and in an intercalator-resistant daughter line, III- 60/AMSA. The new drug was cytotoxic to both lines at doses as low as 50 nM for 1 h./V-(5,5-Diacetoxypentyl)doxorubicin produced DNA interstrand cross-linking in both lines. The cross-linking appeared to increase in both lines following drug treatment, but the increase was greater in the resistant line. This appeared to be due to an underestimation of crosslinking, particularly in sensitive HL-60, secondary to time-dependent DNA fragmentation that followed drug removal. This time-dependent DNA fragmentation was probably endonucleolytic cleavage (a feature of apoptosis) as characteristic nucleosomal ladders were produced by V- (5,5-diacetoxypentyl)doxorubicin treatment in a cotemporal time-depend ent fashion. This novel anthracycline is the tirsi of a family of alkylating anthracyclines designed to be water soluble, easy to formulate, and capable of producing DNA interstrand cross-linking. Because this last characteristic has previously been associated with doxorubicin analogues of great potency and low toxicity, these newer, more readily formulated drugs may have great clinical utility.