published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

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The development and progression of carcinogenesis is a major area of interest to many scientists. Numerous factors, including both environmental and genetic have been implicated in the causation of cancer. It is clear that both these factors and others contribute to neoplastic development and progression. Microsatellites are short tandem repeat sequences which are located in the intron segments of the genome. These noncoding sequences range from 2 to 6 base pairs. An increase or decrease in the number of repeat sequences is referred to as microsatellite instability, also referred to as genetic instability. It is thought that microsatellite instability arises as a result of defects in DNA repair process. During DNA synthesis, the DNA repair genes ensure that the correct nucleotide is incorporated into the newly synthesised DNA strand, so when a mismatch base is incorporated, this is promptly removed and replaced with the correct base. However, if the repair system is defective this would give rise to numerous genetic aberrations along that region of the genome. Recently, microsatellite instability and allelic imbalance/loss of heterozygosity have been shown to play an important role in the development of many cancers, especially colorectal cancer (CRC) associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. This study was undertaken to investigate microsatellite instability and allelic imbalance in colorectal and oesophageal carcinomas in the KwaZulu Natal region of South Africa. The molecular analysis was correlated with clinicopathological data to establish a baseline level on which further studies could be performed. In addition, this study represents the first fluorescent based microsatellite analysis of these two common cancers in South Africa. Normal and tumour DNA was isolated from formalin fIxed paraffin embedded tissue. Fluorescent-based DNA technology using an automated DNA sequencer (Alf Express Automated DNA Sequencer) was employed. CY5 labelled primers for microsatellite markers (DCC, D18S34, D18S58, D3S659, D2S123 and D3S1255) were used. The data was captured and analysed using the Fragment Manager Software. The informativity of the microsatellite markers used in this study ranged from 50% to 71.8%. LOH/AI in the region of the DCC gene in the under 35 years of age CRC was 39.1%, while MSI in this region occurred in 31.25% of cases. The DNA repair gene status in these young patients was as follows: LOH/AI: 31.3% and MSI: 40.4%. In the over 50 years of age CRC, LOH/AI in the 18q region was 28% and MSI was 38%. The DNA repair genes (hMSH2 and hMLH1) in this cohort showed LOH/AI in 24% and MSI also in 24%. As regards oesophageal cancer, LOH/AI in the 18q region was 20.5% and MSI 7.7%. The repair genes showed LOH/AI in 17.9% and MSI in 10.25% of cases. When the molecular events were correlated with clinicopathological features, no statistically significant pattern emerged. However, it must be remembered that relatively small numbers of cases (39) were analysed.In conclusion: • No statistical correlation was found between clinicopathological characteristics and the molecular analysis in either CRC and oesophageal cancer. • LOH/AI and MSI was higher in the under 35 age group. • LOH/AI and MSI in 18q, 2p and 3p in sporadic CRC were similar to other fluorescent-based studies in patients over 50 years of age. • LOH/AI and MSI in 18q, 2p and 3p in oesophageal cancer was similar to studies from other geographical areas. • Finally, fluorescent-based microsatellite PCR and analysis was found to be an objective and efficient technique. / Thesis (Ph.D.)-University of Natal, 1998.

Errata pages inserted behind leaf 293. / Includes bibliography (leaves 255-293). / xv, 293, [60] leaves, [33] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to determine the molecular mechanism by which expression of Fas is lost in colorectal tumours and investigates the effects of re-introducing Fas into colon cancer cells. An animal study was undertaken in addition to the studies of colorectal cancer, to investigate the role of Fas signalling in hormone-dependent involution of the prostate gland. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 1998?

Errata pages inserted behind leaf 293. / Includes bibliography (leaves 255-293). / xv, 293, [60] leaves, [33] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to determine the molecular mechanism by which expression of Fas is lost in colorectal tumours and investigates the effects of re-introducing Fas into colon cancer cells. An animal study was undertaken in addition to the studies of colorectal cancer, to investigate the role of Fas signalling in hormone-dependent involution of the prostate gland. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 1998?

Introduction: Gastric and colon cancer are major causes of mortality and morbidity worldwide. Gastric cancer is often detected at an advanced stage and current chemotherapeutics are only modestly effective against this neoplasm. Novel chemotherapeutics, chemopreventive agents and treatment strategies are required to prevent and treat gastric cancer. The ideal method to eliminate cancer cells may be the induction of apoptosis, further preventing cell proliferation and tumour growth. Recently, short-chain fatty acids (SCFAs) butyrate and propionate have been investigated as potential chemotherapeutic agents, particularly in colon cancer. Butyrate is reported to induce apoptosis in colon cancer cells and is demonstrated to modulate intracellular redox state by altering the levels of an antioxidant, glutathione (GSH). GSH availability is controlled by the oxidative pentose pathway (OPP). Very few studies have investigated the effects of butyrate on cell types other than colon cancer cells, and even less is known regarding the effects of propionate. This thesis investigated the potential for SCFAs to induce apoptosis in a gastric cancer cell line, Kato III, compared to the colon cancer cell line, Caco-2. Cell cycle regulation, OPP activity, GSH availability and glucose metabolism were also assessed. Methods: Initial studies developed a new technique to measure 1-13C-D-glucose metabolism. Following this, Kato III and Caco-2 colon carcinoma cells were treated with butyrate or propionate (1mM, 5mM or 10mM) or a 5mM combination of both SCFAs. The induction of apoptosis and cell cycle alterations by these SCFAs were assessed using flow cytometry. OPP activity and GSH availability were assessed in both cell lines using colorimetric techniques. Butyrate metabolism was assessed using 13C-butyrate. Results: Butyrate and propionate significantly induced apoptosis and G2-M arrest in Kato III and Caco-2 cells, although to a significantly greater extent in the latter cell line. Moreover, butyrate induced apoptosis to a significantly greater extent than propionate, in both cell lines. SCFA treatment led to the significant up-regulation of OPP activity in both cancer cell lines while GSH availability was significantly reduced. Glucose metabolism was initially increased by all SCFA treatments, however, 72hr butyrate treatment led to its reduction. Importantly, glucose metabolism was measured using a new technique developed within this thesis. The rate of butyrate metabolism was demonstrated to correlate with the sensitivity of each cell line to this SCFA. Conclusions: This thesis provides evidence that SCFAs, particularly butyrate, induce apoptosis in gastric and colon cancer cells in vitro. The response of cancer cells to SCFAs appears complex, and involves multiple distinct mechanisms and pathways, including p53, Fas, changes to intracellular redox state and glucose metabolism. The capability of butyrate to induce apoptosis also appears to be directly related to the rate of its metabolism. Butyrate has the potential to be utilised as an adjunctive therapy for the treatment of gastric cancer and colon cancer. / Thesis (Ph.D.) -- School of Molecular and Biomedical Science, 2007

Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (Ph. D. in Cancer Biology)--Vanderbilt University, Dec. 2006. / Title from title screen. Includes bibliographical references.

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