Whitehouse, Pauline Amanda;
(2005)
Integrated individualised treatment of colorectal cancer.
Doctoral thesis , UCL (University College London).
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Abstract
Introduction: Advanced colorectal cancer (CRC) has a poor prognosis with a 5-year survival of only 5% despite treatment with chemotherapeutic agents. The ATP- Tumour Chemosensitivity Assay (ATP-TCA) has been used to demonstrate heterogeneity of chemosensitivity between tumours of the same tissue type, but this has been difficult to establish in colorectal cancer due to infection of cells in culture. Methods: The ex vivo ATP-TCA was modified with antibiotics for use in CRC, and with immunohistochemistry and quantitative RT-PCR, has been used to assess the chemosensitivity and resistance of CRC tumour-derived cells. Results: (a) The addition of 2.5 mug/ml amphotericin B and 1 mug/ml metronidazole to culture media did not effect the cytotoxicity of all drugs tested on SK-MEL-28 melanoma cell lines. (b) The metabolite of irinotecan, SN38, was found to be inactive in the ATP-TCA (c) The ATP-TCA was performed on 71 CRC samples, 58 of which were evaluable (82%). There was considerable heterogeneity for individual samples and drugs tested. (d) Mitomycin C + gemcitabine was the most effective combination in 78% of specimens, with all but one sample showing sensitivity. The synergistic effect between these two drugs was not found to be schedule-specific. (e) Molecular studies determined the expression of a number of molecular targets which were correlated with the ATP-TCA results. The only correlation found was between positive staining for topoisomerase I and sensitivity to irinotecan. (f) Using qRT-PCR it was found that cyclo-oxgenase2 is up-regulated by short-term exposure to 5-fluorouracil (3-fold), but down-regulated by irinotecan (2.5-fold). Conclusion: The results show that it is possible to perform the ATP-TCA on CRC tumour-derived cells with a high evaluability rate. The changes in gene expression after short-term drug exposure have important implications for the use of sequential therapy in the treatment of colorectal and cancers.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Integrated individualised treatment of colorectal cancer |
| Identifier: | PQ ETD:602826 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1446884 |
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