Khelifi, Amel Feriel; (2003) Haemoxygenase in tumours and its role in vascular targeting with combretastatin a4 phosphate. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The present thesis describes in vitro and in vivo investigations into the role of haemoxygenase (HO) in tumours and in vascular targeting by the novel tubulin binding agent combretastatin A4-phosphate (CA-4-P). HO catalyses the degradation of haem, producing the biologically active molecules iron, bilirubin and carbon monoxide. HO-1, one of the three isozymes of HO, is induced in response to stress and in pathological conditions including cancer, inflammation and vascular injury and plays an important role in cytoprotection. CA-4-P binds to tubulin causing disruption of microtubule function leading to destabilisation of the cell cytoskeleton. In vivo, CA-4-P causes vascular collapse and haemorrhagic necrosis in various tumour models. HO-1 protein levels were found to be high in rodent and xenografted tumour models. Further investigations demonstrated only a minor role played by the HO system in sustaining tumour growth and in the maintenance of tumour blood flow in the rat P22 tumour model. In vivo, administration of CA-4-P at a clinically relevant dose caused induction of HO-1 in a sub-group of treated P22 rat tumours, as analysed by immunohistochemistry. HO-1 positive staining was localised in perinecrotic areas and tumour-associated macrophages were the predominant cell type expressing the protein. In vitro, CA-4-P exposure had greater anti-proliferative effects in P22 tumour cells than HUVECs, and the latter showed faster recovery of a distinct tubulin cytoskeleton than the former. Furthermore, CA-4-P caused a much more pronounced HO-1 induction in P22 tumour cells than in HUVECs. The antioxidant N-acetyl-L-cysteine (NAC) completely blocked CA-4-P-mediated HO-1 induction in tumour cells suggesting that CA-4-P is causing an imbalance in the redox state of cells possibly via glutathione depletion. Finally, combination therapy with the HO inhibitor tin protoporphyrin IX (SnPP) and CA- 4-P tended to improve the efficacy of CA-4-P alone in the P22 rat and CaNT mouse tumour models. This combination requires further investigation.

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