A STUDY OF THE MECHANISM OF VASOACTIVE DRUGS ON TUMOR BLOOD FLOW RATE
Abstract
The literature indicates that tumor vasculator contains broad sinusoids that lack the smooth muscle necessary for vasomotion. The ability to increase the therapeutic ratio through the manipulation of tumor blood flow rate would be highly advantageous in cancer therapy. The aim of this research was to study the mechanism of direct-acting vasoactive drugs on tumor blood flow rate and to develop a model that can be used to predict the response of other tumors to these drugs. Prior to the vasoactive drug study, two methods were derived to determine the accuracy of the microsphere technique itself and the adequacy of the 15 micron diameter microspheres used for measuring tumor blood flow rate. When known flow was mechanically perfused through isolated systemic circulation of rats, accuracy of the microsphere technique is measuring this flow rate was found to be 97% with a 0.22 correlation. This result confirmed the fact that the microsphere technique can be used to detect physiological changes. The 15 (+OR-) 3 micron diameter microspheres were found to be adequate for measuring blood flow rate in the two tumor types, "hard" and "soft", used in the vasodrug studies. Regional blood flow and cardiac output were measured in 150-250 g rats bearing subcutaneous nodules of two types of transplantable carcinoma ("hard" and "soft") with microscopically different vascular patterns. Three groups of rats were treated either with hydralazine (H, 0.1 mg/100g i.v., n = 17) 0.9% Saline (S, 0.3 ml, n = 11, controls), or phenylephrine (PE, 0.005 mg/100g i.v., n = 17) and regional blood flow determined at the time of maximum blood pressure response. Results were correlated with quantitative morphometric analysis of arteriolar and capillary wall thickness in tumor and normal tissues. Phenylephrine decreased and hydralazine increased normal tissue perfusion as measured by cardiac output. Tumor blood flow remained low and was not significantly influenced by drug treatment, except for the phenylephrine effect on the "hard" tumors. Histological study of tumor vessel walls revealed an absence of smooth muscle capable of responding to the vasoactive drugs by constriction or dilation. By comparing the results of the two tumor types used, the overall effects of vasoactive drugs was shown to be depended upon the microvasculature of both the tumor and the surrounding normal tissues.
Degree
Ph.D.
Subject Area
Surgery
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