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. |
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dc.language.iso |
en |
en |
dc.publisher |
ResearchSpace@Auckland |
en |
dc.relation.ispartof |
PhD Thesis - University of Auckland |
en |
dc.relation.isreferencedby |
UoA9910984314002091 |
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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 |
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dc.type |
Thesis |
en |
thesis.degree.grantor |
The University of Auckland |
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thesis.degree.level |
Doctoral |
en |
thesis.degree.name |
PhD |
en |
dc.rights.holder |
Copyright: The author |
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dc.identifier.wikidata |
Q112848567 |
|