Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II

K. M. Tewey, G. L. Chen, E. M. Nelson, Leroy-Fong Liu

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Abstract

Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells. Using purified mammalian DNA topoisomerase II, we have demonstrated that the antitumor drugs ellipticine and 2-methyl-9-hydroxyellipticine (2-Me-9-OH-E+) can produce reversible protein-linked DNA breaks in vitro. 2-Me-9-OH-E+ which is more cytotoxic toward L1210 cells and more active against experimental tumors than ellipticine is also more effective in stimulating DNA cleavage in vitro. Similar to the effect of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) on topoisomerase II in vitro, the mechanism of DNA breakage induced by ellipticines is most likely due to the drug stabilization of a cleavable complex formed between topoisomerase II and DNA. Protein denaturant treatment of the cleavable complex results in DNA breakage and covalent linking of one topoisomerase II subunit to each 5'-end of the cleaved DNA. Cleavage sites on pBR322 DNA produced by ellipticine or 2-Me-9-OH-E+ treatment mapped at the same positions. However, many of these cleavage sites are distinctly different from those produced by the antitumor drug m-AMSA which also targets at topoisomerase II. Our results thus suggest that although mammalian DNA topoisomerase II may be a common target of these antitumor drugs, drug-DNA-topoisomerase interactions for different antitumor drugs may be different.

Original languageEnglish
Pages (from-to)9182-9187
Number of pages6
JournalJournal of Biological Chemistry
Volume259
Issue number14
Publication statusPublished - 1984
Externally publishedYes

Fingerprint

Reunion
Type II DNA Topoisomerase
ellipticine
Antineoplastic Agents
DNA
Amsacrine
DNA Breaks
Ellipticines
Type I DNA Topoisomerase
DNA Cleavage
Proteins
Pharmaceutical Preparations
Cultured Cells
Tumors
Stabilization
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. / Tewey, K. M.; Chen, G. L.; Nelson, E. M.; Liu, Leroy-Fong.

In: Journal of Biological Chemistry, Vol. 259, No. 14, 1984, p. 9182-9187.

Research output: Contribution to journalArticle

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