Spatial heterogeneity of tumour blood flow modification induced by angiotensin II: Relationship to receptor distribution

Abstract

Angiotensin II (ATII) has potential for improving delivery of blood-borne anti-cancer agents to tumours by increasing tumour blood flow. However, ATII-induced hypertension is not always accompanied by an increase in tumour blood flow due to significant constriction of the tumour vasculature. Such unpredictability in tumour response to ATII limits the clinical usefulness of this approach. In this study, the potential of assessing numbers of binding sites for ATII as a predictor of tumour blood flow response to intravenous administration of ATII was investigated. The distribution of ATII receptors in the rat P22 carcinosarcoma was related to tumour blood flow distribution and blood flow response to ATII using an autoradiographic approach. ATII (0.2 microgram x kg-1 x min-1) increased mean arterial blood pressure of anaesthetized BD9 rats from 92.2 +/- 1.4 mmHG to 145.6+- 1.3 mmHg. Despite this increase in perfusion pressure, overall tumour blood flow to viable regions decreased by 20%, indicating significant constriction of tumour blood vessels. Autoradiographic localisation of tumour blood flow showed that the decrease in flow was confined to the tumour periphery, with no change at the tumour centre. This pattern was consistent with 10% more binding sites for ATII at the tumour periphery than at the tumour centre. Maximum number of binding sites (BLmax) for the P22 tumour was 0.38 +/- 0.09 fmol x mg-1, which is approximately a factor of 10 lower than published values for various normal tissues. The dissociation constant Kd was l.16 +/- 0.18 nM. These results encourage the development of techniques for analysis of receptor binding characteristics for predicting the response of individual tumours to blood flow manipulation using vasoactive agents.