UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

An investigation of chemoresistance of liver cancers using the comet assay and isolated organ perfusion systems

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). Green open access

[thumbnail of U592517.pdf] Text
U592517.pdf

Download (24MB)

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.

Type: Thesis (Doctoral)
Title: An investigation of chemoresistance of liver cancers using the comet assay and isolated organ perfusion systems
Identifier: PQ ETD:592517
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/1445199
Downloads since deposit
196Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item