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Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II.

Abstract
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.
AuthorsL A Zwelling, J Mayes, E Altschuler, P Satitpunwaycha, T R Tritton, M P Hacker
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 46 Issue 2 Pg. 265-71 (Jul 20 1993) ISSN: 0006-2952 [Print] England
PMID8394077 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anthraquinones
  • Intercalating Agents
  • Isoquinolines
  • Quinolones
  • Topoisomerase II Inhibitors
  • 5,8-bis(2-aminoethylamino)-1-azaanthracene-9,10-dione
  • DNA
  • DNA Topoisomerases, Type II
  • pixantrone
Topics
  • Anthraquinones (pharmacology)
  • DNA (metabolism)
  • DNA Topoisomerases, Type II (metabolism)
  • Drug Resistance
  • Humans
  • Intercalating Agents (pharmacology)
  • Isoquinolines (pharmacology)
  • Leukemia (enzymology)
  • Quinolones
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured (drug effects)

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