Shankar-Chowdhury, Arjun; (1999) The role of vasoactive agents in the treatment and development of colorectal liver metastases. Doctoral thesis (M.B.B.S), UCL (University College London).

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Abstract

The blood vessels supplying colorectal liver metastases lack both a smooth muscle layer and neuronal innervation. Co-administration of vasoconstricting agents with hepatic arterial therapy should therefore cause blood to be shunted from the liver into the tumour and hence improve drug delivery. One such vasoconstricting agent, endothelin-1 (ET-1), in addition to its actions as a vasomodulator may also play a role in the regulation of the growth of both primary and secondary colorectal cancers. The aims of this thesis were to study: firstly, the effects of hepatic arterial infusion of vasoconstricting agents on liver and tumour blood flow and drug delivery in a animal model of colorectal liver metastases and secondly to determine whether ET-1 is produced by cell types within colorectal liver metastases using immuno- electronmicroscopy and also measure whether such production translates into elevated plasma levels in patients with colorectal cancer with and without liver metastases. Although the vasoconstricting agents caused a transitory elevation in the tumour/normal blood flow ratio only noradrenaline produced improvements in drug uptake. A variety of cell types within the tumour were found to produce ET-1 and the plasma levels of ET-1 were elevated in both groups of cancer patients. Use of vasopressor agents may allow improvements in hepatic arterial chemotherapy, whilst application of antagonists to ET-1 may play a role in the treatment of colorectal cancer.

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