Cytosine arabinoside lesions are position-specific topoisomerase II poisons and stimulate DNA cleavage mediated by the human type II enzymes

Cytosine arabinoside (araC) is an important drug used for the treatment of human leukemias. In order to exert its cytotoxic effects, araC must be inco rporated into chromosomal DNA,Although specific DNA lesions that involve ba se loss or modification stimulate nucleic acid cleavage mediated by type II topoisomerases, the effects of deoxyribose sugar ring modification on enzy me activity have not been examined. Therefore, the effects of incorporated araC residues on the DNA cleavage/religation equilibrium of human topoisome rase II alpha and beta were characterized. AraC lesions were position-speci fic topoisomerase II poisons and stimulated DNA scission mediated by both h uman type II enzymes. However, the positional specificity of araC residues differed from that previously reported for other cleavage-enhancing DNA les ions. Finally, additive or synergistic increases in DNA cleavage were obser ved in the presence of araC lesions and etoposide. These findings broaden t he range of DNA lesions known to alter topoisomerase II function and raise the possibility that this enzyme may mediate some of the cellular effects o f araC.