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Determining the effect of DNA repair capacity on chemotherapy toxicity during colorectal cancer treatment

Webster, Richard 2015. Determining the effect of DNA repair capacity on chemotherapy toxicity during colorectal cancer treatment. PhD Thesis, Cardiff University.
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This study describes the translation of an assay developed for use in cell culture models to into a method of measuring patterns of DNA damage from platinum agents in human blood samples. These adduct patterns could potentially be used in future studies for the stratification of patients for response and toxicity to oxaliplatin chemotherapy. Chapters 3 and 4 of this thesis describe the steps taken to translate our DIP--‐chip assay, a tool previously used in the study of DNA repair capacity in yeast and to measure induction of platinum-DNA adducts in cell culture models, into an assay capable of reproducibly analysing chemotherapy damage in human clinical samples. These results clearly demonstrate the protocol modifications required to use the assay on human blood samples, and show the reproducibly of the assay in detecting patterns of oxaliplatin induced DNA-adducts in clinical material. Chapter 5 describes the development of novel bioinformatic tools and analysis methods for interpreting DIP--‐chip DNA--‐adduct microarray outputs. The translation of a genomic--‐scale laboratory technology into a tool for patient stratification is a technical and bioinformatics challenge. The tools developed are a significant advance on previously available bioinformatic functions, and are essential for the application of this technique as a clinically useful assay. The final results section, chapter 6, documents the successful development of functional models to experimentally confirm links between single nucleotide polymorphisms in nucleotide excision repair genes with the development of oxaliplatin induced peripheral neuropathy (OIPN). This aspect of the study utilises new information, recently derived from experiments DNA-sequencing colorectal cancer patients, to develop a functional model of OIPN in Saccharomyces cerevisiae. This model is then used to demonstrate the impact of variations in DNA repair genes on the development of OIPN ‐ a relationship that highlights the significance of DNA repair to the development of oxaliplatin toxicity.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Jun 2019 02:50

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