FROM HYDRALAZINE TO CGRP TO MAN

Attempts to selectively reduce tumour blood flow have, in the past, co ncentrated on the use of hydralazine. However, although this vasodilat or can be highly effective in experimental animals, it is only at such high concentration as to result in a severe and clinically unacceptab le reduction in systemic blood pressure. At clinically acceptable leve ls, the drug appears to produce a small increase in tumour blood flow. We have used the techniques of magnetic resonance spectroscopy as ind icators of metabolism and blood flow in a search for vasoactive drugs that would produce an effective reduction in tumour blood flow without causing severe hypotension or other serious side effects. Single inje ctions of either prazosin or CGRP are shown to be substantially more e ffective than hydralazine in causing a reduction in tumour blood flow without massive reduction in blood pressure. Even more effective was C GRP given by continuous infusion. In this case a three-fold reduction in tumour blood flow could be obtained with a reduction of only 15-20% in systemic blood pressure. All these studies, however, have been mad e with transplanted animal tumours. Using high-dose hydralazine and pr imary tumours that were either radiation or chemically induced, we obt ained a success rate of only about a 35% in causing selective reductio n in blood flow. In contrast, in a transplanted tumour line derived fr om one of the non-responding radiation-induced primary lesions, the su ccess rate was about 95%, consistent with the majority of animal studi es using transplanted tumours. An implication of this finding is that the results of vascular studies on transplanted tumours may not necess arily be extrapolated directly to spontaneous tumours. Whether or not this is the case for CGRP needs to be investigated in man.