Medicine (Austin & Northern Health) - Theses
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ItemTargeting therapy in colon cancer( 2011)Colon cancer is a common disease affecting Australians and is rarely curable once metastatic disease develops. Angiogenesis plays an important role in the development of metastases. In metastatic colon cancer, anti-angiogenesis agents such as bevacizumab have been integrated in to standard clinical practice. Despite only a modest benefit in delaying disease progression, these agents are expensive and associated with rare but catastrophic side effects, including cerebrovascular accident, pulmonary embolus and intestinal perforation. Standard treatments for metastatic colon cancer still consist of chemotherapy that is not targeted to cancer cells and affects all dividing cells in the body, including those in bone marrow, gastrointestinal tract and hair follicles, causing significant toxicity. In order to improve the toxicity of drugs such as doxorubicin, they have been encapsulated in nanoparticles, which are small structures usually smaller than 1µm in size. The aim of the first study was to investigate differences in the expression of angiogenic factors in the epithelium and stroma of normal colon, primary colon cancer and metastatic colon cancer. The hypothesis was that angiogenic factors would be upregulated in metastases compared with primary tumours and normal colon. Archival samples of primary colon cancer, adjacent normal colon and an associated metastasis were obtained from 32 patients. Immunohistochemistry was used to examine the tumours for vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)-2 expression. In the primary tumour, VEGF-A levels were significantly higher in tumour cells compared with the stroma but there was not a difference in expression between normal colon and cancer. The aim of the second study was to measure the changes in circulating biomarkers and circulating endothelial precursor cells (CEPC) in patients commencing treatment with chemotherapy and an angiogenesis inhibitor for metastatic colon cancer. The hypothesis was that biomarkers of angiogenesis would decrease as a result of treatment and that there would be a difference in biomarker levels between patients who responded and those who did not. Plasma biomarkers were measured in patients prior to treatment and then every two weeks for six weeks. There was a non-significant correlation between placental growth factor (PlGF) and basic fibroblast growth factor (bFGF) and tumour bulk as well as a significant correlation between CEPC and VEGF-A. In addition, CEPC fell in patients who responded poorly to treatment whereas those who did respond had low CEPC at baseline that did not change. The aim of the third study was to determine the biodistribution of a variety of hollow polymeric nanoparticles and measure the changes in biodistribution and tumour uptake that occurred as a result of coating with polyethylene glycol (pegylation) and antibody functionalisation. The hypothesis was that alteration in size and surface chemistry would affect biodistribution and that pegylation and antibody functionalisation would increase tumour uptake and reduce uptake by other organs. Biodistribution in mice of nanoparticles made using a layer-by-layer technique from poly(vinylpyrrolidone) (PVP), poly(methacrylic acid) (PMA) or DNA showed high liver and spleen uptake. This occurred despite alterations in size, polymer type and pegylation. Positron emission tomography (PET) and Gamma Camera imaging demonstrated that liver uptake of nanoparticles is nearly instantaneous and fluorescent microscopy showed that Kupffer cells were the cell-type responsible for uptake. Short circulation time appeared to be responsible for poor tumour uptake. Attaching the human A33 antibody, that specifically binds colon cancer cells, to PVP nanoparticles, appeared to reduce liver and spleen uptake but did not result in significant tumour uptake.