Murine transgenic cells lacking DNA topoisomerase IIβ are resistant to acridines and mitoxantrone: Analysis of cytotoxicity and cleavable complex formation Journal Article


Authors: Errington, F.; Willmore, E.; Tilby, M. J.; Li, L.; Li, G.; Li, W.; Baguley, B. C.; Austin, C. A.
Article Title: Murine transgenic cells lacking DNA topoisomerase IIβ are resistant to acridines and mitoxantrone: Analysis of cytotoxicity and cleavable complex formation
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 II/3 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 II -/- cells compared with topo IIβ +/+ cells was observed after treatment with amsacrine (mAMSA), methyl N-(4'- [9-acridinylamino]-2-methoxyphenyl) carbamate hydrochloride (AMCA), methyl N- (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.
Keywords: dna-binding proteins; nonhuman; antineoplastic agents; drug targeting; animal cell; mouse; animals; mice; cell survival; cells, cultured; complex formation; etoposide; cytotoxicity; drug resistance; transgenic mouse; mice, transgenic; antigens, neoplasm; mitoxantrone; amsacrine; dna topoisomerase (atp hydrolysing); acridine derivative; acridines; isoenzymes; dna topoisomerases, type ii; dna topoisomerases, type ii, eukaryotic; priority journal; article
Journal Title: Molecular Pharmacology
Volume: 56
Issue: 6
ISSN: 0026-895X
Publisher: The American Society for Pharmacology and Experimental Therapeutics  
Date Published: 1999-01-01
Start Page: 1309
End Page: 1316
Language: English
PUBMED: 10570059
PROVIDER: scopus
DOI: 10.1124/mol.56.6.1309
DOI/URL:
Notes: Article -- Export Date: 16 August 2016 -- Source: Scopus
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MSK Authors
  1. Ligeng Li
    18 Li
  2. Gloria C Li
    119 Li