Flavone acetic acid and 5,6-dimethylxanthenone-4-acetic acid: relationship between plasma nitrate elevation and the induction of tumour necrosis.

Antitumour agents such as flavone acetic acid, xanthenone acetic acid (XAA), 5,6-dimethylxanthenone-4-acetic acid and tumour necrosis factor-alpha, following single dose administration to mice with colon 38 adenocarcinomas, induce tumour haemorrhagic necrosis and an elevation in plasma nitrate. The relationship between these two effects has been studied using firstly a series of methyl-substituted XAA derivatives with varying antitumour activity, and secondly the inhibitors NG-monomethyl-L-arginine (NMMA), N-nitro-L-arginine (NNA) and canavanine, which affect nitric oxide synthesis. Elevation of plasma nitrate resulting from the oxidation of L-arginine by nitric oxide synthase is inhibited by NNA rather than by NMMA or canavanine. The results demonstrate that tumour necrosis can be induced in the absence of a significant elevation of plasma nitrate.