Medicine (Austin & Northern Health) - Theses
Permanent URI for this collection
Search Results
1 - 2 of 2
-
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.
-
ItemHypoxia and angiogenesis in renal cell carcinoma( 2009)Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans. Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16 Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated. Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17 Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18 Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.