Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II.
We have examined the activities of two novel aza-anthracene-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 to 2-aza but not to 1-aza, whereas the resistant HL-60/AMSA was sensitive to neither agent. Measurements of 1- and 2-aza-induced, topoisomerase II-mediated DNA cross-linking in the cells revealed patterns of resistance and sensitivity that paralleled the results in the cytotoxicity assays. However, measurements of drug-induced topoisomerase II-mediated DNA cross-linking using purified HL-60 and HL-60/AMSA topoisomerase II indicated that both agents could stabilize a covalent complex between DNA and the HL-60 enzyme. HL-60/AMSA topoisomerase II resisted stabilization by either agent. This suggests that the resistance of HL-60 cells to 1-aza is not due to the inability of this drug to inhibit topoisomerase II but rather to another, undefined mechanism.
Zwelling
L A
LA
Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
Mayes
J
J
Altschuler
E
E
Satitpunwaycha
P
P
Tritton
T R
TR
Hacker
M P
MP
D000880:Anthraquinones / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D007938:Leukemia / Q000201:enzymology; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000880:Anthraquinones; D007364:Intercalating Agents; D007546:Isoquinolines; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C082542:5,8-bis(2-aminoethylamino)-1-azaanthracene-9,10-dione; D004247:DNA; D004250:DNA Topoisomerases, Type II; C086548:pixantrone