Spalding, Duncan Richard Castell; (2008) An investigation of chemoresistance of liver cancers using the comet assay and isolated organ perfusion systems. Doctoral thesis , UCL (University College London).

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Abstract

Current approaches to selecting new chemotherapies are inadequate. In vitro tissue culture models ignore the tumour microenviroment whilst murine models do not mimic human cancers. The aim of this thesis was to develop an isolated, perfused and oxygenated human liver tumour model to investigate the short term effects of chemotherapeutic agents used in the treatment of liver cancer. Expression of drug resistance transporter proteins was evaluated in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cell lines and did not correlate with drug resistance. P-glycoprotein (P-gp), when present, failed to demonstrate significant function. The comet assay demonstrated tumour DNA damage with chemotherapy and DNA-adduct repair with cisplatin. An orthotopic model of human liver cancer in nude mice evaluated the topographic distribution of cisplatin DNA-adducts by the comet assay in vivo. This was correlated with the presence of tumour proliferation, hypoxia, vascularity and P-gp expression determined by immunohistochemistry. Rates of repair of DNA-adducts were both quantitatively and qualitatively different from in vitro data, and superficial tumour cells were more efficient at repair in comparison with deep cells. An isolated, dual perfused liver cancer model was then developed in both the rat and human. In both models livers remained viable whilst on the perfusion circuit. Differences were observed in the timing of maximal DNA damage between drugs, and DNA damage was dose dependent. Chemotherapy induced greater tumour DNA damage in superficial as compared to deep portions of the cancers. This thesis has investigated the chemoresistance of liver cancers and developed a unique methodology for investigating human liver cancers using an ex vivo perfusion model. New insight into early DNA damage with chemotherapy has been demonstrated but more importantly the scientific basis established for a new approach to refining conventional therapies or evaluating new biological cancer therapies.

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