In many cancers, a chronic increase in oxidant stress - associated with elevated 
levels of hydrogen peroxide - contributes to the increased proliferative rate, 
diminished apoptosis, increased angiogenic and metastatic capacity, and 
chemoresistance that often characterize advanced malignancies. This oxidant 
stress often reflects up-regulation of expression and activity of NADPH oxidase, 
and/or decreased activity of catalase, which functions as suppressor gene in 
oxidant-dependent cancers. These characteristics of oxidant-dependent cancers 
suggest a dual strategy for treatment of these cancers. Since ascorbate can 
react spontaneously with molecular oxygen to generate hydrogen peroxide, 
high-dose intravenous ascorbate should be selectively toxic to tumors that are 
low in catalase activity - as suggested by numerous cell culture studies. 
Measures which concurrently improve the oxygenation of hypoxic tumor regions 
would be expected to boost the efficacy of such therapy; calcitriol and 
high-dose selenium might also be useful in this regard. Secondly, during the 
intervals between sessions of ascorbate therapy, administration of agents which 
can safely inhibit NADPH oxidase would be expected to slow the proliferation and 
spread of surviving tumor cells - while providing selection pressure for a 
further decline in catalase activity. In effect, cancers treated in this way 
would be whipsawed between lethally excessive and inadequately low oxidant 
stress. An additional possibility is that ascorbate-induced oxidant stress in 
tumors might potentiate the cell kill achieved with concurrently administered 
cytotoxic drugs, inasmuch as oxidant mechanisms appear to play a mediating role 
in the apoptosis induced by many such drugs, largely via activation of c-Jun 
NH(2)-terminal kinase; cell culture studies would be useful for evaluating this 
possibility.