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Research ArticleArticle

Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation

F. Errington, E. Willmore, M. J. Tilby, L. Li, G. Li, W. Li, B. C. Baguley and C. A. Austin
Molecular Pharmacology December 1999, 56 (6) 1309-1316; DOI: https://doi.org/10.1124/mol.56.6.1309
F. Errington
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E. Willmore
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M. J. Tilby
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L. Li
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G. Li
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W. Li
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B. C. Baguley
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C. A. Austin
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Abstract

Murine transgenic cell lines lacking DNA topoisomerase II (topo II)β have been used to assess the importance of topo IIβ as a drug target. Western blot analysis confirmed that the topo IIβ −/− cell lines did not contain topo IIβ protein. In addition, both the topo IIβ +/+ and topo IIβ −/− cell lines contained similar levels of topo IIα protein. The trapped in agarose DNA immunostaining assay (TARDIS) was used to detect topo IIα and β cleavable complexes in topo IIβ −/− and topo IIβ +/+ cells. These results show that both topo IIα and β are in vivo targets for etoposide, mitoxantrone, and amsacrine (mAMSA) in topo IIβ +/+ cells. As expected, only the α-isoform was targeted in topo IIβ −/− cells. Clonogenic assays comparing the survival of topo IIβ −/− and topo IIβ +/+ cells were carried out to establish whether the absence of topo IIβ caused drug resistance. Increased survival of topo IIβ −/− cells compared with topo IIβ +/+ cells was observed after treatment with amsacrine (mAMSA), methylN-(4′-[9-acridinylamino]-2-methoxyphenyl) carbamate hydrochloride (AMCA), methylN-(4′-[9-acridinylamino]-2-methoxyphenyl)carbamate hydrochloride (mAMCA), mitoxantrone, and etoposide. These studies showed that topo IIβ −/− cells were significantly more resistant to mAMSA, AMCA, mAMCA, and mitoxantrone, than topo IIβ +/+ cells, indicating that topo IIβ is an important target for the cytotoxic effects of these compounds.

Footnotes

    • Received June 7, 1999.
    • Accepted September 15, 1999.
  • Send reprint requests to: Dr. C. A. Austin, School of Biochemistry and Genetics, The Medical School, The Cookson Building, Newcastle upon Tyne, NE2 4HH, UK. E-mail: caroline.austin{at}ncl.ac.uk

  • F. Errington is supported by a Gordon Piller Studentship from the Leukemia Research Fund (Grant 9683); Dr. E. Willmore is supported by the Leukemia Research Fund (Grant 9743); and Dr. M. J. Tilby is supported by the North of England Children's Cancer Research Fund.

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Molecular Pharmacology: 56 (6)
Molecular Pharmacology
Vol. 56, Issue 6
1 Dec 1999
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Research ArticleArticle

Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation

F. Errington, E. Willmore, M. J. Tilby, L. Li, G. Li, W. Li, B. C. Baguley and C. A. Austin
Molecular Pharmacology December 1, 1999, 56 (6) 1309-1316; DOI: https://doi.org/10.1124/mol.56.6.1309

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Research ArticleArticle

Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation

F. Errington, E. Willmore, M. J. Tilby, L. Li, G. Li, W. Li, B. C. Baguley and C. A. Austin
Molecular Pharmacology December 1, 1999, 56 (6) 1309-1316; DOI: https://doi.org/10.1124/mol.56.6.1309
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