Effect of 1-β- D-arabinofuranosylcytosine (ara-C) on nuclear topoisomerase II activity and on the DNA cleavage and cytotoxicity produced by 4'-(9-acridinylamino)methanesulfon- m-anisidide (m-AMSA) and etoposide in m-AMSA-sensitive and -resistant human leukemia cells

Abstract

The ability of a noncytotoxic dose of ara-C to modulate the amount of 4'-(9-acridinylamino)-methanesulfon- m-anisidide ( m-AMSA)- or etoposide-induced topoisomerase II-mediated DNA cleavage and cytotoxicity was examined in m-AMSA-sensitive and -resistant HL-60 human leukemia cells. Ara-C pretreatment (0.1 μM × 48 hr) sensitized m-AMSA-sensitive cells to the cytotoxicity and DNA cleavage produced by both m-AMSA and etoposide. The actions of m-AMSA in the m-AMSA-resistant cells were affected minimally by ara-C. By contrast, ara-C enhanced etoposide-induced DNA cleavage and, to an even greater extent, etoposide-induced cytotoxicity in m-AMSA-resistant cells. These cells were only minimally cross-resistant to etoposide. Ara-C did not affect the cellular uptake of m-AMSA or etoposide, the amount of 0.35 M NaCl-extractable nuclear topoisomerase II activity from either cell line, or the ability of this enzyme activity to covalently bind to DNA in the presence of the drugs. m-AMSA- and etoposide-induced DNA cleavage is thought to result from drug-induced stabilization of a topoisomerase II-DNA complex. The ability of ara-C to modulate this effect and associated cytotoxicity appears to be mediated by the effects of ara-C on cellular targets other than topoisomerase II but which are important to topoisomerase II-mediated events, such as protein-associated DNA cleavage. A good candidate for such a target may be cellular chromatin.