Toggle Main Menu Toggle Search

Open Access padlockePrints

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 Willmore, Dr Michael Tilby, Professor Caroline Austin

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.


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


Actions

Find at Newcastle University icon    Link to this publication


Share