Mechanism of antitumor drug action: Poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide

E. M. Nelson, K. M. Tewey, Leroy-Fong Liu

Research output: Chapter in Book/Report/Conference proceedingChapter

464 Citations (Scopus)

Abstract

The intercalative acridine derivative 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), but not its isomer o-AMSA, is a potent antitumor drug that in mammalian cells stimulates the formation of DNA strand breaks that are characterized by tightly bound proteins. Using purified mammalian DNA topoisomerases, we have analyzed the effects of these antitumor drugs on topoisomerase-DNA interactions. The antitumor drug m-AMSA dramatically stimulates the formation of a topoisomerase II-DNA complex that is detected on protein-denaturant treatment: both single- and double-stranded DNA breaks are produced and a topoisomerase II subunit is linked covalently to each 5' end of the broken DNA strands. The noncytotoxic isomer, o-AMSA, which does not induce significant amounts of DNA breaks in cultured cells, exhibits a correspondingly smaller effect in stimulating formation of the complex in vitro. The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange.

Original languageEnglish
Title of host publicationISOTOPENPRAXIS
Pages1361-1365
Number of pages5
Volume20
Edition1
Publication statusPublished - 1984
Externally publishedYes

Fingerprint

Type II DNA Topoisomerase
Amsacrine
Antineoplastic Agents
Poisoning
DNA Breaks
DNA
DNA Topoisomerases
Acridines
Single-Stranded DNA Breaks
Type I DNA Topoisomerase
Sister Chromatid Exchange
Double-Stranded DNA Breaks
Gene Rearrangement
Cultured Cells
Proteins
Pharmaceutical Preparations
In Vitro Techniques
4'-(9-acridinylamino)methanesulfon-o-anisidide

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mechanism of antitumor drug action : Poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide. / Nelson, E. M.; Tewey, K. M.; Liu, Leroy-Fong.

ISOTOPENPRAXIS. Vol. 20 1. ed. 1984. p. 1361-1365.

Research output: Chapter in Book/Report/Conference proceedingChapter

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