A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters of Science in Medicine (Pharmacology) Johannesburg, 2013 / Colon cancer is the third most common cancer worldwide and the second most common in the western world. More than 40 % of colon cancer sufferers develop metastases and chemotherapy is often used alone or in combination with radiotherapy as adjunctive therapy for the advanced disease. A major effort has been made in the past decade to develop anticancer agents through both empiric screening and rational design of new compounds. These attempts are made to improve the survival rate, reduce the severe adverse effects associated with existing cancer chemotherapeutic agents as well as to reduce the development of drug resistance. In the present study, two colon cancer cell lines were exposed to novel imidazo[1,2-a]pyridines and novel nucleoside analogues, aiming to investigate the cytotoxic efficacy on the cells, the mode of cell death, and to explore the pathways by which cell death was induced.

Colorectal cancer has a 9.8% cumulative incidence rate, making it the third most common cancer in the Western world. Despite a 50-60% response rate in patients to current cancer therapies, drug resistance and tumour relapse remain a concern. While current therapies reduce the tumour mass, they possibly fail to eradicate a unique population of pluripotent tumour resident cells. These cells, known as cancer stem cells, may have similar properties of self-renewal and proliferation to embryonic and adult stem cells, as they also express a number of key pluripotent transcription factors, including amongst others, NANOG, OCT3/4 and SOX2. Furthermore, since discreet groups of such stem cells are proposed to essentially drive tumourigenesis, they present as potential novel targets for cancer therapy. This study aimed to isolate a putative CSC population from the advanced colon adenocarcinoma cell lines HT29 and DLD1 and to assess the therapeutic effects of the epigenetic drugs Valproic acid and Zebularine on pluripotent gene expression.

by Anthony Tak Cheung Chan. / "March 1998." / Thesis (M.D.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (p. 200-242). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstract in Chinese.

Thesis (M.S.)--University of Michigan, 1987.

Thesis (M.S.)--University of Michigan, 1983.

Thesis (M.S.)--University of Michigan, 1987.

Thesis (M.S.)--University of Michigan, 1987.

Thesis (M.S.)--University of Michigan, 1983.

Cis-platinum is a widely used cytotoxic agent with known radiosensitising properties. It is used in the treatment of various types of lung cancer that may include radiation to the lung as part of the treatment protocol. There is little evidence and some conflict as to whether it sensitises pulmonary tissue to the effects of radiation treatment. This project investigates the effect of cis-platinum alone or in combination with radiation on mouse lung. Four end points were used to evaluate treatments. They were: the release of pulmonary surfactant, changes in breathing rate, a histology based score of damage and changes in TGF-β - a cytokine important in the development of fibrosis. Single doses of either cis-platinum or radiation, cis-platinum given immediately before a single dose of radiation, cis-platinum given immediately before the first of two fractions of radiation and cis-platinum given at various times before and after a single dose of radiation were investigated. Cis-platinum alone was observed to cause an increase in the phospholipid content of lavaged surfactant. Cis-platinum was observed to cause an early release in surfactant and a trend existed for it to induce an early increase in breathing rates as compared to that induced by radiation alone. Cis-platinum was observed to increase radiation damage as assessed using a histology based scoring system. Higher TGF-β levels in lavaged surfactant were observed in C57 /Bl mice as compared to Balb/C. No difference in TGF-β levels was seen in homogenised lung between the strains. Cis-platinum may cause changes in TGF-β in C57/Bl mice but further work is necessary to confirm this.

Breast cancer is the most common cancer among females and it is the leading cause of death in mid-age women. Epidemiological studies indicate that Asian women have a lower incidence of breast cancer compared with their counterparts in the West, which soy consumption has been suggested as a contributory factor. Soy and soy-based food contain a rich amount of phytoestrogens, which are suggested to be protective against cancer. Cyclooxygenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid to prostaglandins. Recent studies have revealed that up-regulation of cyclooxygenase-2 (COX-2), an isoform of COX, plays an important role in tumorigenesis and metastasis. COX-2 may facilitate carcinogenesis in a number of means, may include altering cell proliferation and apoptosis, enhancing angiogenesis and suppressing immune surveillance. Clinical examinations of breast cancer specimens indicated that COX-2 is overexpressed. In the present study, we investigated the effect of flavonoids on COX-2 expression in human breast cells. / Our results showed that daidzein and its metabolite eqoul, genistein, butein, isoliquiritigenin (ILN) and apigenin could inhibit phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in breast cells MCF-7 and MCF-10A. The inhibitory effects were in concentration-dependent manners. Real-time PCR and western blot analysis showed that the flavonoids suppressed the induced mRNA and protein expression. Suppression could be observed in concentration as low as 0.1 muM. Luciferase reporter assay indicated that the inhibition was at the gene transactivation level. Further investigation using truncated hCOX-2 promoter plasmids revealed that the AP-1 site (-67/-61) and cyclic AMP response element (CRE) site (-59/-53) on hCOX-2 promoter were responsible for the suppression. Electrophoretic mobility shift assay results further confirmed that the flavonoids acted through inhibiting AP-1/CREB DNA binding to suppress the expression. / To examine the possible upstream signal transduction pathways involved, inhibitors of protein kinase A (PKA), protein kinase (PKC) and mitogen activated protein kinase (MAPK) were employed. Reporter gene assay revealed a possible involvement of ERK1/2 MAP kinase in AP-1 and/or CRE activation of hCOX-2 promoter. Taken together, these results suggested that the phytochemicals down-regulated PMA-induced COX-2 expression by counteracting AP-1 and CRE sites via the modulation of MAPK pathway. The findings might have significant implications in the chemopreventive and chemotherapeutic applications of flavonoids in breast cancer. / Lau, Tak Yi. / "December 2007." / Adviser: Lai Kwok Leung. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4734. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 142-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.