dc.contributor.advisor |
Burns, K |
en |
dc.contributor.advisor |
Helsby, N |
en |
dc.contributor.author |
Neuberger, Daniel |
en |
dc.date.accessioned |
2018-07-19T04:31:07Z |
en |
dc.date.issued |
2018 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/37508 |
en |
dc.description |
Full text is available to authenticated members of The University of Auckland only. |
en |
dc.description.abstract |
The fluoropyrimidine 5-fluorouracil (5-FU) has become a cornerstone in the treatment of colorectal and breast cancer since its development over 60 years ago. Unfortunately, its use is often complicated by severe (grade 3-4) toxicities, that can often be dose limiting. Inherited deficiencies in key metabolic enzymes important in the elimination or activation of 5-FU fail to explain a large percentage of the toxicity observed clinically, and it is hypothesised that catastrophically high cellular uptake of the drug in certain individuals may be an additional predisposing factor. The aim of this thesis was to investigate the transport of 5-FU into normal buccal mucosal cells. The germline exomes of 13 candidate drug transporters were examined in 22 cancer patients undergoing fluoropyrimidine chemotherapy, and the relationship between each patient’s single nucleotide polymorphisms (SNPs) and toxicity profile was scrutinised. The phenotypic inter- and intra-individual variability in 5-FU uptake into buccal mucosal cells was then probed two cohorts of participants: 1) healthy individuals and 2) patients undergoing fluoropyrimidine treatment for gastrointestinal or breast cancer. Primary buccal mucosal cells were collected by cytobrush and incubated in uptake buffer with radiolabelled [14C]5-FU (5 μM) for 5 minutes at 37 °C. A subset of healthy participants (n=16) were re-tested either weekly or monthly over 20 weeks. The differential mRNA expression of an extended panel of 88 candidate drug transporters was investigated in pooled buccal samples collected from individuals with high versus low 5-FU uptake. No SNPs identified within the candidate genes were significantly associated with 5-FU toxicity. 5-FU uptake was variable, ranging from 0.11 pmol.min-1.105 live cells-1 to 19.18 pmol.min-1.105 live cells-1 across the individuals at the first test. Retesting of healthy participants indicated that these values, while reproducible in one participant (5FU026), varied significantly in the other 15 volunteers over time (p < 0.05). Age and gender accounted for a small proportion of this observed variability (0.77% and 4.82%, respectively). Of the 88 transporters examined, 32 had no detectable mRNA expression and only SLC7A5 was differentially expressed between the high and low uptake pools (p = 0.0226). |
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dc.publisher |
ResearchSpace@Auckland |
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dc.relation.ispartof |
Masters Thesis - University of Auckland |
en |
dc.relation.isreferencedby |
UoA99265072011902091 |
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dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights |
Restricted Item. Available to authenticated members of The University of Auckland. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ |
en |
dc.title |
Exploration of the variation in different transporters on fluoropyrimidine toxicity and the differential uptake of 5-FU into buccal mucosal cells |
en |
dc.type |
Thesis |
en |
thesis.degree.discipline |
Biomedical science |
en |
thesis.degree.grantor |
The University of Auckland |
en |
thesis.degree.level |
Masters |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.elements-id |
748048 |
en |
pubs.record-created-at-source-date |
2018-07-19 |
en |
dc.identifier.wikidata |
Q112937676 |
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