Drug resistance in human tumor cells

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dc.contributor.advisor Judd, W. en
dc.contributor.author Snow, Karen en
dc.date.accessioned 2007-09-10T05:33:35Z en
dc.date.available 2007-09-10T05:33:35Z en
dc.date.issued 1988 en
dc.identifier THESIS 88-165 en
dc.identifier.citation Thesis (PhD--Cellular and molecular biology)--University of Auckland, 1988 en
dc.identifier.uri http://hdl.handle.net/2292/1775 en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Resistance of tumor cells to chemotherapy is a major obstacle for successful treatment of cancers. In this study, clonal sublines of the Jurkat human T lymphoblastoid cell line were used to develop several sublines resistant to 2 clinically available drugs, amsacrine and adriamycin. Resistant sublines were extensively characterized in an attempt to elucidate mechanism(s) of resistance involved. Results and conclusions may be summarized as follows: - cells selected for resistance to either amsacrine or adriamycin showed strong cross resistance to several other drugs which shared inhibition of topoisomerase II as a common mechanism of action; cross resistance to unrelated drugs was comparatively low - agents previously shown by others to reverse resistance in several drug resistant cell lines did not modulated resistance of Jurkat sublines - overexpression of the 170K MW Pgp (a membrane glycoprotein associated with drug transport) was not detected in resistant cells - rigorous analyses proteins expressed in drug resistant and control Jurkat sublines revealed differences between resistant and sensitive cells in the expression of 15-20K MW and 85K MW proteins (although many more non resistance-associated differences between sublines were observed) - reduced levels of drug accumulation or retention did not effect resistance in the 2 sublines tested for this alteration - an agent which depletes intracellular glutathione levels potentiated adriamycin cytotoxicity in a subline selected for adriamycin resistance, however, the putative phenotypic change in resistant cells responsible for this effect was not identified and the phenotype was not stable - components of the GSH detoxification system as well as several other potential drug metabolizing enzymes had similar activities in resistant and control sublines - thin layer chromatography of daunorubicin metabolites generated by cell homogenates revealed differences between resistant and control cells, possibly caused by reduced aldo keto reductase activity or an altered drug-binding component in resistant cells - evidence for a significant level of gene amplification in resistant cells was not found; in addition no correlation was observed between the presence of marker chromosomes or specific chromosomal aberrations and the presence of the drug resistance phenotype - drug resistant sublines were significantly resistant to drug-induced formation of DNA breaks and protein-DNA complexes, although drug –DNA binding was not reduced - catalytic activity of topoisomerase II in resistant compared with control cells showed several qualitative and quantitative differences. In conclusion, it seems likely that resistance of at least 2 of the drug resistant sublines developed in this study was mediated by a modified DNA-drug-topoisomerase II association, possibly due to quantitatively and/or qualitatively altered topoisomerase II. en
dc.language.iso en en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA9910984314002091 en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Drug resistance in human tumor cells en
dc.type Thesis en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en


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