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Vasoactive manipulation to enhance the delivery and uptake of regional infusion chemotherapy in the treatment of colorectal hepatic metastases.

Dworkin, Michael Jonathan; (1996) Vasoactive manipulation to enhance the delivery and uptake of regional infusion chemotherapy in the treatment of colorectal hepatic metastases. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Hepatic arterial infusion chemotherapy for colorectal hepatic metastases increases tumour response rates and prolongs survival. Despite this response rates remain at approximately 50[percent]. Vasoactive manipulation has been proposed as a strategy to increase the proportion of blood flow and consequently cytotoxic uptake to the tumour. This study was designed to assess the changes in liver and tumour perfusion in response to a variety of vasoactive agents in a rat liver metastasis model. Laser Doppler flowmetry was used to assess the perfusion changes over a period of time. Vasopressin and angiotensin II led to a rapid onset hepatic vasoconstriction for a short period after which restoration of flow occurred despite continued infusion of the vasoconstrictor agent. Endothelin I had the most prolonged effect as a hepatic vasoconstrictor and at increasing the tumour to normal ratio. Nitric oxide inhibition led to a gradual onset and mild degree of vasoconstriction. However the tachyphylaxis seen in response to vasopressin could be prevented or reversed by the coadministration of a nitric oxide inhibitor. In a separate experiment, blood flow and 5FU uptake ratios were measured at a single time point following a 30 minute infusion of a vasoactive agent. There was a close correlation between blood flow and 5FU uptake ratios, implying that strategies to enhance the proportion of blood flow to the tumour would also increase the uptake of 5FU. A range of vasoconstrictor and capillary permeability agents were assessed following a 30 minute infusion. Of the agents tested, angiotensin II and endothelin I were found to produce a significant increase in blood flow and 5FU uptake ratios by approximately two fold. In conclusion, infusion of vasoconstrictor agents may be used to increase blood flow and 5FU uptake ratios. This effect varies between agents and varies throughout the duration of the infusion. Despite an increase in blood flow ratios, there was no absolute increase in tumour blood flow and tumours remained hypovascular in relation to surrounding liver parenchyma.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Vasoactive manipulation to enhance the delivery and uptake of regional infusion chemotherapy in the treatment of colorectal hepatic metastases.
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10105154
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