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.
Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030.
L A
LA
Zwelling
J
J
Mayes
E
E
Altschuler
P
P
Satitpunwaycha
T R
TR
Tritton
M P
MP
Hacker
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