Abstract
Cell lines resistant to adriamycin and amsacrine were derived from cloned sublines of the human T cell line Jurkat. Most of the lines resemble atypical MDR cells (Danks et al., 1987; Beck et al., 1987). Thus, resistant Jurkat sublines were cross resistant to several topoisomerase II inhibiting drugs but had low or no resistance to other classes of drugs, resistance was not reversed by verapamil, Pgp was not overexpressed, and drug accumulation was unaltered in resistant compared to parental (control) sublines. Other findings were that anthracycline metabolism differed between resistant and parental sublines, and that resistant sublines displayed altered expression of small polypeptides (less than 20K MW) and an 85K MW protein. Drug resistant cells showed resistance to the production of drug induced cytogenetic aberrations, DNA breaks, and protein-DNA complexes. Resistance was not mediated by altered binding of drugs to DNA or by increased repair of DNA damage. Indirect evidence suggests that the resistant cells had an altered drug-DNA-topoisomerase II association. The study highlights the complex relationships between DNA breaks, cytogenetic aberrations, protein-DNA complexes and drug cytotoxicity, and shows that the relationships differ for adriamycin and amsacrine, suggesting some differences in the modes of action and/or resistance for the drugs and cell lines.
Highlights
The term 'atypical MDR' was coined by Danks et al (1987) to describe cells cross resistant to several topoisomerases inhibiting drugs but sensitive to Vinca alkaloids
R factors for amsacrine or adriamycin were unaffected by 10 iLM verapamil, 10 !M chlorpromazine or 5l ml1' amphotericin B
Development of resistance to adriamycin or amsacrine was accompanied by cross resistance to several other drugs, the resistant Jurkat sublines characterised in detail here did not display the MDR phenotype previously described by others (Beck, 1987; Moscow & Cowan, 1988; Bradley et al, 1988)
Summary
The term 'atypical MDR' was coined by Danks et al (1987) to describe cells cross resistant to several topoisomerases inhibiting drugs but sensitive to Vinca alkaloids. Resistance of these human leukaemic cells was not mediated by increased drug efflux, and neither Pgp expression nor mdr transcripts were detected (Danks et al, 1987; Beck et al, 1987). In other reports of resistance (Pommier et al, 1986; Per et al, 1987) or hypersensitivity (Robson et al, 1987) to topoisomerase II inhibiting drugs, it has been suggested that quantitatively or qualitatively altered topoisomerase II or a topoisomerase II modifying activity affects the altered production of drug-induced protein-associated DNA breaks observed in such cells
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