The molecular effects of low dose fractionated radiation treatment on Ovarian Adenocarcinoma

Brandon, Jason Anthony (2004) The molecular effects of low dose fractionated radiation treatment on Ovarian Adenocarcinoma. Doctoral thesis, University of Central Lancashire.

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Ovarian cancer is the second most common gynaecologic malignancy and the leading cause of death from gynaecologic cancer. Only one fifth of women present with an early stage (stages I or II) of the disease, whereas the remainder have an advanced stage (stages HI or IV) of the disease at the time of diagnosis. Although a significant improvement in response rate has occurred with the advent of platinum or Taxol based chemotherapy, there has not been a marked improvement in survival. These therapies often fail because tumour cells acquire resistance to therapy through mutation: and altered expression of cellular genes. The aim of this project was to investigate a radiation treatment regime that could overcome the clinical problem of radioresistance. Recently, it has been shown in cell survival studies that low doses of radiation (less than 100cGy) induce an initial phase of hypersensitivity (HRS) to radiation in vitro. This HRS is most pronounced in radioresistant cells.
A treatment regime involving 0.5 Gy radiation dose given 4 times with 8 hour intervals between doses, delivered alone and in combination with the chemotherapeutic agent Taxotere was effective in both radiosensitive (BO-!) and radioresistant (SW626) cell lines. This low dose fractionated treatment (LDFRT) was effective in reducing cellular surviving fractions of these cell lines irrespective of the cellularp53 status. The molecular mechanism for LDFRT mediated sensitisation was
investigated through the use of a protein DNA array. It was observed that an estrogen response element (ERE) and one of its target genes, Lipocalin 2, which is known to be involved in the growth and differentiation of cells, were not induced as a result of LDFRT, but induction was observed after treatment with a single dose of 2 Gy radiation. This observation indicates a possible molecular mechanism whereby LDFRT is more effective than single dose radiation in overcoming radioresistance. This project potentially represents a major paradigm shift in radiation delivery, which could significantly impact on future treatment strategies for ovarian and other cancers.

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