Role of nitric oxide in growth of solid tumours: a balancing act.

NO synthases are unique among eukaryotic enzymes in being dimeric, calmodulin-dependent or calmodulin-containing cytochrome P-450-like haemoproteins that combine reductase and oxygenase catalytic domains in one monomer. They catalyse the formation of NO from L-arginine in the presence of NADPH and molecular oxygen. There are, broadly, three distinctive forms of NO synthase, of which two are constitutively expressed in a variety of cells and are calcium dependent. Of these, the endothelial cell-specific form (eNOS) can play an important role in vascular development, maintenance of vascular tone and tumour growth. A third, inducible, calcium-independent form (iNOS), is important in the immunogenic and cytotoxic response of T-lymphocytes and macrophages. NO acts as an intracellular secondary messenger and provides an efficient system for cellular regulation, interaction and defence, while striking a very fine balance in its role in tumour growth and--under some circumstances--appearing to promote tumour growth, whereas other evidence suggests its production can be growth inhibitory. Nevertheless, tumour cells do express both the constitutive and inducible forms of NO synthase, albeit at widely different levels, and their presence in some human cancers correlates positively with tumour grade. Its role is strictly dependent upon its chemical reactivity with oxygen and metals, e.g. in haem-containing proteins, rather than specific structural interactions with physiological targets. Conflicting evidence still surrounds the effects of expressing high levels of iNOS activity and consequent production of NO on tumour growth. Similar conflicting results have been obtained by applying various NO donors and NO synthase inhibitors. Overall, NO may be acting as part of a signalling cascade for neovascularization in vivo, whereas in vitro cytotoxic properties contribute to the 'apparent' slowing of the growth of cells. It is our contention that low concentrations of NO can be pro-angiogenic and pro-tumour growth, whereas higher NO concentrations can have the opposite effect. Like many other areas of therapeutics, the concept of dose-response is very important. Modification of NO synthase activity in tumours, and hence NO biosynthesis, may be regarded as a promising means for selective tumour blood flow modification and provides a novel approach for reducing tumour oxygenation aimed at enhancing the efficiency of hypoxia-mediated, bioreductively activated anti-cancer drugs.