The physiological importance and therapeutic potential of nitric oxide in the tumour-associated vasculature

Abstract

Abstract The relationship between malignant tumours and their vascular supply differs in many respects from that of most normal tissues. Tumour vasculature is characterized by rapid proliferation (1,2), increased permeability (3,4), and disorganized architecture (5-8), properties which are both a cause and a consequence of inadequate perfusion and oxygenation (9). We may summarize the condition of tumour vasculature as a system that is maximally stimulated, yet still unable to meet the metabolic demands of the tissue it supplies. The consequences of this for cancer therapy are profound (I 0,11 ). An inadequate vascular network leads to a heterogeneous blood supply and to areas within most tumours that are deprived of the limiting metabolic substrate, oxygen (12-14). This in turn creates regions with radiobiologically hypoxic cells which are both resistant to radiotherapy and quiescent. The lack of proliferative activity protects them from many chemotherapeutic drugs which are proliferation-dependent in their cytotoxic action. It should occasion no surprise then, that the influence of vasoactive agents on tumour blood flow has received considerable attention over the last 20 years (15,16) and this approach is still seen as a mechanism through which the action of anti-cancer agents could be enhanced. This review will focus on the importance of one highly topical vasoactive molecule, nitric oxide (NO). While the importance of this molecule in cancer therapy generally has been considered in a recent review (17) we will focus on its role in tumour-associated vasculature and evaluate its potential as a target for cancer therapy in this context.