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

Lookup NU author(s): Fiona Errington, Dr Elaine WillmoreORCiD, Dr Michael Tilby, Professor Caroline AustinORCiD


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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.

Publication metadata

Author(s): Errington F, Willmore E, Tilby MJ, Li L, Li G, Li W, Baguley B, Austin CA

Publication type: Article

Publication status: Published

Journal: Molecular Pharmacology

Year: 1999

Volume: 56

Issue: 6

Pages: 1309-1316

Print publication date: 01/01/1999

ISSN (print): 0026-895X

ISSN (electronic): 1521-0111

Publisher: American Society for Pharmacology and Experimental Therapeutics

PubMed id: 10570059