N-(5,5-diacetoxypentyl)doxorubicin: a novel anthracycline producing DNA interstrand cross-linking and rapid endonucleolytic cleavage in human leukemia cells.

Abstract

The cytotoxic and DNA-damaging effects of a novel alkylating anthracycline, N-(5,5-diacetoxypentyl)doxorubicin, were quantified in HL-60 human leukemia cells and in an intercalator-resistant daughter line, HL-60/AMSA. The new drug was cytotoxic to both lines at doses as low as 50 nM for 1 h. N-(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 cross-linking, 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 N-(5,5-diacetoxypentyl)doxorubicin treatment in a cotemporal time-dependent fashion. This novel anthracycline is the first 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.