Back to Search
Start Over
Murine Transgenic Cells Lacking DNA Topoisomerase IIβ Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation
- Source :
- Molecular Pharmacology. 56:1309-1316
- Publication Year :
- 1999
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 1999.
-
Abstract
- Murine transgenic cell lines lacking DNA topoisomerase II (topo II)beta have been used to assess the importance of topo IIbeta as a drug target. Western blot analysis confirmed that the topo IIbeta -/- cell lines did not contain topo IIbeta protein. In addition, both the topo IIbeta +/+ and topo IIbeta -/- cell lines contained similar levels of topo IIalpha protein. The trapped in agarose DNA immunostaining assay (TARDIS) was used to detect topo IIalpha and beta cleavable complexes in topo IIbeta -/- and topo IIbeta +/+ cells. These results show that both topo IIalpha and beta are in vivo targets for etoposide, mitoxantrone, and amsacrine (mAMSA) in topo IIbeta +/+ cells. As expected, only the alpha-isoform was targeted in topo IIbeta -/- cells. Clonogenic assays comparing the survival of topo IIbeta -/- and topo IIbeta +/+ cells were carried out to establish whether the absence of topo IIbeta caused drug resistance. Increased survival of topo IIbeta -/- cells compared with topo IIbeta +/+ 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 IIbeta -/- cells were significantly more resistant to mAMSA, AMCA, mAMCA, and mitoxantrone, than topo IIbeta +/+ cells, indicating that topo IIbeta is an important target for the cytotoxic effects of these compounds.
- Subjects :
- Amsacrine
Cell Survival
Antineoplastic Agents
Mice, Transgenic
Biology
Mice
chemistry.chemical_compound
Antigens, Neoplasm
medicine
Animals
Topoisomerase II Inhibitors
Cytotoxic T cell
Cytotoxicity
Clonogenic assay
Cells, Cultured
Etoposide
Pharmacology
Mitoxantrone
Topoisomerase
Virology
Molecular biology
DNA-Binding Proteins
Isoenzymes
DNA Topoisomerases, Type II
chemistry
Cell culture
biology.protein
Acridines
Molecular Medicine
DNA
medicine.drug
Subjects
Details
- ISSN :
- 15210111 and 0026895X
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....07bb8e1aa4f4c2f91be3fa739b7e9061