ACTIVITY OF 2 NOVEL ANTHRACENE-9,10-DIONES AGAINST HUMAN LEUKEMIA-CELLS CONTAINING INTERCALATOR-SENSITIVE OR INTERCALATOR-RESISTANT FORMS OF TOPOISOMERASE-II

We have examined the activities of two novel azaanthracene-9,10-diones (aza), 1-aza and 2-aza, in HL-60 human leukemia cell lines containing type II topoisomerases with different sensitivities to inhibition by other intercalating agents. The sensitive line, HL-60, was sensitive t o 2-aza but not to 1-aza, whereas the resistant HL-60/AMSA was sensiti ve to neither agent. Measurements of 1- and 2-aza-induced, topoisomera se II-mediated DNA cross-linking in the cells revealed patterns of res istance and sensitivity that paralleled the results in the cytotoxicit y assays. However, measurements of drug-induced topoisomerase II-media ted DNA cross-linking using purified HL-60 and HL-60/AMSA topoisomeras e II indicated that both agents could stabilize a covalent complex bet ween DNA and the HL-60 enzyme. HL-60/AMSA topoisomerase II resisted st abilization by either agent. This suggests that the resistance of HL-6 0 cells to 1-aza is not due to the inability of this drug to inhibit t opoisomerase 11 but rather to another, undefined mechanism.