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Keywords: metabonomics, metabolomics, bladder cancer, gas chromatography mass spectrometry, two dimensional gas chromatography, chemometrics
Issue Date: 5-Aug-2010
Abstract: Bladder cancer (BC) is the 7th most common cancer worldwide. Although BC is not usually fatal, it is characterized by frequent recurrences that can progress to more invasive disease. The recurrence rates of BC are as high as 50-70%, therefore, life-long close surveillance is needed. This renders BC a very expensive cancer to treat. Cystoscopy is considered the gold standard for the clinical diagnosis of human BC. As cystoscopy is expensive and invasive, it may compromise patients¿ compliance and account for the failure in detecting recurrent BC in some patients. Urinary cytology is commonly used for the noninvasive detection of BC. While it has a good sensitivity for poorly differentiated tumors, especially for carcinoma in situ, the sensitivity for low grade papillary urothelial carcinoma is low. Moreover cytology results are not available immediately and are interpreter dependent. Large panels of markers have been investigated to achieve an improvement in noninvasive diagnostics. However, the markers do not have the specificity and sensitivity of cystoscopy. As such, alternative noninvasive diagnostic methods for BC such as the use of biomarkers become important. Metabonomics is a burgeoning science bringing together analytic technology, metabolite evaluation, and computation. The integration of this tool into current biomarker research programs gives us an opportunity to screen for biomarkers related to BC. In this thesis, we investigated the role of urinary metabonomics in the diagnosis of human BC using multianalytical platforms. In addition, in vitro molecular changes in BC were characterized using nontumorigenic and tumorigenic human urothelial cells. Urine samples collected from BC patients and non-BC subjects were subjected to GC/TOFMS, NMR and GC×GC/TOFMS analysis. The acquired data were subjected to chemometric data analysis such as principal component analysis and orthogonal partial least squares discriminant analysis. Furthermore, feasibility of distinguishing different stages or grades of the BC using urinary profiles was also investigated. Advantages and drawbacks of each analytical platform in urinary metabonomic analysis were examined. BC patients were clearly distinguished from non-BC subjects based on their global urinary metabolic profiles. Significantly higher sensitivity in detecting BC was observed using urinary metabonomics compared to urinary cytology. Additionally, urinary metabonomics exhibited early potential in the staging and grading of bladder tumors. Although the relationship between these results and the physiological or biochemical mechanisms involved remains unclear, this thesis confirmed that there exist endogenous metabolites in the patients¿ urine, which could be promising markers for BC detection. The findings were further supported by metabonomic analysis of BC cell culture media samples. The use of multiple analytical methods aided the identification of a broader spectrum of important metabolites associated with BC. In addition, GC×GC/TOFMS was demonstrated as a powerful tool for analyzing both in vitro metabolic footprinting cell medium and complex urine samples. Application of GC×GC offered several advantages including enhanced chromatographic resolution (without increase in analytical run time), improved identification of metabolites and also separation of reagent artifacts from the metabolite peaks. In summary, urinary metabonomics is amenable for the noninvasive diagnosis of human BC.
Appears in Collections:Ph.D Theses (Open)

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