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

G. L. Chen, L. Yang, T. C. Rowe, B. D. Halligan, K. M. Tewey, Leroy-Fong Liu

Research output: Contribution to journalArticle

615 Citations (Scopus)

Abstract

Many intercalative antitumor drugs have been shown to cleave DNA indirectly through their specific effect on the stabilization of a cleavable complex formed between mammalian DNA topoisomerase II and DNA. Antitumor epipodophyllotoxins (VP-16 and VM-26) which do not intercalate DNA can similarly induce protein-linked DNA breaks in cultured mammalian cells. In vitro studies using purified mammalian DNA topoisomerase II show that epipodophyllotoxins interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II by stabilizing a cleavable complex. Treatment of this stabilized cleavable complex with protein denaturants results in DNA strand breaks and the covalent linking of a topoisomerase subunit to the 5'-end of the broken DNA. Furthermore, epipodophyllotoxins also inhibit the strand-passing activity of mammalian DNA topoisomerase II, presumable as a result of drug-enzyme interaction. The agreement between the in vivo and in vitro studies suggest that mammalian DNA topoisomerase II is a drug target in vivo. The similarity between the effect of epipodophyllotoxins on mammalian DNA topoisomerase II and the effect of nalidixic acid on Escherichia coli DNA gyrase suggests that the cytotoxic action of epipodophyllotoxins may be analogous to the bactericidal action of nalidixic acid.

Original languageEnglish
Pages (from-to)13560-13566
Number of pages7
JournalJournal of Biological Chemistry
Volume259
Issue number21
Publication statusPublished - 1984
Externally publishedYes

Fingerprint

Reunion
Type II DNA Topoisomerase
Podophyllotoxin
Antineoplastic Agents
DNA
Nalidixic Acid
DNA Breaks
Teniposide
DNA Gyrase
Etoposide
Drug Interactions
Pharmaceutical Preparations
Escherichia coli
Cultured Cells
Proteins
Stabilization
Cells
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. / Chen, G. L.; Yang, L.; Rowe, T. C.; Halligan, B. D.; Tewey, K. M.; Liu, Leroy-Fong.

In: Journal of Biological Chemistry, Vol. 259, No. 21, 1984, p. 13560-13566.

Research output: Contribution to journalArticle

Chen, G. L. ; Yang, L. ; Rowe, T. C. ; Halligan, B. D. ; Tewey, K. M. ; Liu, Leroy-Fong. / Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. In: Journal of Biological Chemistry. 1984 ; Vol. 259, No. 21. pp. 13560-13566.
@article{44101e90d53044ffaf419f79a905cf3e,
title = "Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II",
abstract = "Many intercalative antitumor drugs have been shown to cleave DNA indirectly through their specific effect on the stabilization of a cleavable complex formed between mammalian DNA topoisomerase II and DNA. Antitumor epipodophyllotoxins (VP-16 and VM-26) which do not intercalate DNA can similarly induce protein-linked DNA breaks in cultured mammalian cells. In vitro studies using purified mammalian DNA topoisomerase II show that epipodophyllotoxins interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II by stabilizing a cleavable complex. Treatment of this stabilized cleavable complex with protein denaturants results in DNA strand breaks and the covalent linking of a topoisomerase subunit to the 5'-end of the broken DNA. Furthermore, epipodophyllotoxins also inhibit the strand-passing activity of mammalian DNA topoisomerase II, presumable as a result of drug-enzyme interaction. The agreement between the in vivo and in vitro studies suggest that mammalian DNA topoisomerase II is a drug target in vivo. The similarity between the effect of epipodophyllotoxins on mammalian DNA topoisomerase II and the effect of nalidixic acid on Escherichia coli DNA gyrase suggests that the cytotoxic action of epipodophyllotoxins may be analogous to the bactericidal action of nalidixic acid.",
author = "Chen, {G. L.} and L. Yang and Rowe, {T. C.} and Halligan, {B. D.} and Tewey, {K. M.} and Leroy-Fong Liu",
year = "1984",
language = "English",
volume = "259",
pages = "13560--13566",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II

AU - Chen, G. L.

AU - Yang, L.

AU - Rowe, T. C.

AU - Halligan, B. D.

AU - Tewey, K. M.

AU - Liu, Leroy-Fong

PY - 1984

Y1 - 1984

N2 - Many intercalative antitumor drugs have been shown to cleave DNA indirectly through their specific effect on the stabilization of a cleavable complex formed between mammalian DNA topoisomerase II and DNA. Antitumor epipodophyllotoxins (VP-16 and VM-26) which do not intercalate DNA can similarly induce protein-linked DNA breaks in cultured mammalian cells. In vitro studies using purified mammalian DNA topoisomerase II show that epipodophyllotoxins interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II by stabilizing a cleavable complex. Treatment of this stabilized cleavable complex with protein denaturants results in DNA strand breaks and the covalent linking of a topoisomerase subunit to the 5'-end of the broken DNA. Furthermore, epipodophyllotoxins also inhibit the strand-passing activity of mammalian DNA topoisomerase II, presumable as a result of drug-enzyme interaction. The agreement between the in vivo and in vitro studies suggest that mammalian DNA topoisomerase II is a drug target in vivo. The similarity between the effect of epipodophyllotoxins on mammalian DNA topoisomerase II and the effect of nalidixic acid on Escherichia coli DNA gyrase suggests that the cytotoxic action of epipodophyllotoxins may be analogous to the bactericidal action of nalidixic acid.

AB - Many intercalative antitumor drugs have been shown to cleave DNA indirectly through their specific effect on the stabilization of a cleavable complex formed between mammalian DNA topoisomerase II and DNA. Antitumor epipodophyllotoxins (VP-16 and VM-26) which do not intercalate DNA can similarly induce protein-linked DNA breaks in cultured mammalian cells. In vitro studies using purified mammalian DNA topoisomerase II show that epipodophyllotoxins interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II by stabilizing a cleavable complex. Treatment of this stabilized cleavable complex with protein denaturants results in DNA strand breaks and the covalent linking of a topoisomerase subunit to the 5'-end of the broken DNA. Furthermore, epipodophyllotoxins also inhibit the strand-passing activity of mammalian DNA topoisomerase II, presumable as a result of drug-enzyme interaction. The agreement between the in vivo and in vitro studies suggest that mammalian DNA topoisomerase II is a drug target in vivo. The similarity between the effect of epipodophyllotoxins on mammalian DNA topoisomerase II and the effect of nalidixic acid on Escherichia coli DNA gyrase suggests that the cytotoxic action of epipodophyllotoxins may be analogous to the bactericidal action of nalidixic acid.

UR - http://www.scopus.com/inward/record.url?scp=0021749639&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021749639&partnerID=8YFLogxK

M3 - Article

VL - 259

SP - 13560

EP - 13566

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -