Amplification of oxidative stress by decarboxylation: a new strategy in anti-tumour drug design.

Experimental resu!ts reported in the literature suggest that tumour cells are under oxidative stress, both as a consequence of their altered biochemistry and of the tumour environment. Unfortunately, tumour cells are able to resist this oxidative stress. The cause for their exceptional resistance may be a low content of unsaturated fatty acids or a high level of antioxidants in the cell membrane or the over-expression of the bcl-2 gene [1,2]. We hypothesise that tumour oxidative stress can be amplified by compounds that upon oxidation are converted via a free radical mechanism to species that are more damaging than the initial oxidant, either because they are more reactive or because they can migrate to react at critical sites in the cell. To test this hypothesis under carefully controlled conditions, we have developed a chemical model in which a peroxidase (from horseradish, donor: H202 oxidoreductase, EC 1.1 1.1.7) is used as the oxidant and phosphatidylcholine liposomes as the target. The liposomes are labelled with cisparinaric acid, a fluorescent lipid which loses its fluorescence on oxidation and can therefore, be used as a probe for lipid peroxidation [3]. Additionally, thiobarbituric acid reactive substances were detected by the classical procedure. It was found that peroxidase alone caused little damage to the liposomes. However, the compound indole-3-acetic acid (IAA) strongly accelerated the decay of the fluorescence of cisparinaric acid and the formation of thiobarbituric acid reactive substances (Figure 1).