Reduced topoisomerase II activity in multidrug-resistant human non-small cell lung cancer cell lines
| Autor: | Piet Borst, E. Kamst, A.J. Timmerman, G. P. Van Der Schans, M. De Haas, Frank Baas, E. W. H. M. Eijdems, G. C. B. Astaldi Ricotti, J. De Nooij |
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| Přispěvatelé: | Other departments |
| Jazyk: | angličtina |
| Rok vydání: | 1995 |
| Předmět: |
Amsacrine
Cancer Research Lung Neoplasms DNA damage Methylation Carcinoma Non-Small-Cell Lung medicine Tumor Cells Cultured Humans Topoisomerase II Inhibitors RNA Messenger Etoposide P-glycoprotein Cell Nucleus biology Topoisomerase Virology Molecular biology Drug Resistance Multiple Multiple drug resistance DNA Topoisomerases Type II Oncology Cell culture biology.protein Topoisomerase-II Inhibitor medicine.drug Research Article DNA Damage |
| Zdroj: | British Journal of Cancer Scopus-Elsevier British journal of cancer, 71(1), 40-47. Nature Publishing Group |
| ISSN: | 0007-0920 |
| DOI: | 10.1038/bjc.1995.9 |
| Popis: | Multidrug-resistant (MDR) cell lines often have a compound phenotype, combining reduced drug accumulation with a decrease in topoisomerase II. We have analysed alterations in topoisomerase II in MDR derivatives of the human lung cancer cell line SW-1573. Selection with doxorubicin frequently resulted in reduced topo II alpha mRNA and protein levels, whereas clones selected with vincristine showed normal levels of topo II alpha. No alterations of topo II beta levels were detected. To determine the contribution of topo II alterations to drug resistance, topo II activity was analysed by the determination of DNA breaks induced by the topo II-inhibiting drug 4'-(9-acridinylamino)methane-sulphon-m-anisidide (m-AMSA) in living cells, as m-AMSA is not affected by the drug efflux mechanism in the SW-1573 cells. The number of m-AMSA-induced DNA breaks correlated well (r = 0.96) with in vitro m-AMSA sensitivity. Drug sensitivity, however, did not always correlate with reduced topo II mRNA or protein levels. In one of the five doxorubicin-selected clones m-AMSA resistance and a reduction in m-AMSA-induced DNA breaks were found in the absence of reduced topo II protein levels. Therefore, we assume that post-translational modifications of topo II also contribute to drug resistance in SW-1573 cells. These results suggest that methods that detect quantitative as well as qualitative alterations of topo II should be used to predict the responsiveness of tumours to cytotoxic agents. The assay we used, which measures DNA breaks as an end point of topo II activity, could be a good candidate. Images Figure 1 Figure 2 Figure 4 |
| Databáze: | OpenAIRE |
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