¹Gray Cancer Institute, Mount Vernon Hospital, PO Box 100, Northwood, Middlesex HA6 2JR, UK

Correspondence: Professor GM Tozer, Academic Unit of Surgical Oncology, Division of Clinical Sciences, University of Sheffield, Floor K, Royal Hallamshire Hospital, Sheffield S10 2JF, UK. E-mail: g.tozer@sheffield.ac.uk

²Cemazar's current address: Institute of Oncology, Zaloska 2, Ljubljana SI-1000, Slovenia

Revised 25 April 2005; Accepted 20 May 2005; Published online 21 June 2005.

Abstract

The vascular effects of the endothelin B (ET_B) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50–60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET_B binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET_B receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET_A receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET_B receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET_B receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET_B receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.