Modification of tumor blood flow and enhancement of therapeutic effect of ACNU on experimental rat gliomas with angiotensin II

Abstract

Blood flow was measured in transplanted rat gliomas before and during a constant intravenous infusion of angiotensin II using hydrogen clearance methods. The brain tumor models were produced in syngeneic Wister-King-Aptekman male rats with stereotaxic inoculation of ethylnitrosourea-induced glioma cells (KEG-1). Induced hypertension up to 150 mmHg (mean arterial pressure) with the infusion of angiotensin II resulted in a significant increase of blood flow to tumor center compared to the normotensive state (p less than 0.001). Blood flow measured simultaneously in brain tissue of tumor-free contralateral hemisphere did not change. The therapeutic effect of administration of the simultaneous 1-(4-Amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and angiotensin II was evaluated in four experimental groups with the tumor-bearing rats. Twelve days after tumor implantation, the rats were administered angiotensin II to increase the mean arterial blood pressure to 150 mmHg, followed by intravenous injection of ACNU injection. The increased blood pressure was steadily maintained for 20 minutes. The ACNU/induced hypertension group showed a median survival time of 27.0 days, which was significant longer (p less than 0.02) than that of an ACNU treatment group (22.0 days), a hypertension treatment group (19.0 days), or a no treatment group (18.5 days). The enhanced therapeutic effect can be attributed to improving chemotherapeutic drug delivery due to increased blood flow in the tumor.