Nitric oxide in cancer therapeutics: interaction with cytotoxic chemotherapy

Abstract

Nitric oxide is a key second messenger in most tissues, where it is generated at low concentrations, predominantly by the catalytic action of two constitutively expressed isoforms of nitric oxide synthase (NOS). Both of these are found in tumours, but malignancy is also associated with the expression of high levels of the inducible isoform of NOS, which is responsible for generation of high NO(*) concentrations, not associated with normal physiology. This has profound consequences for the aetiology and malignant progression of primary cancer and metastatic dissemination. It also ensures that tumour vasculature remains highly dilated, so maintaining the abnormally high growth rates, characteristic of malignant disease. This dependency on NO(*) can be targeted therapeutically by administering NOS inhibitors to block NO(*) production, so reducing the availability of metabolic substrates and slowing tumour growth. However, there is now clear evidence that the effects of NO(*) in tumours are bimodal such that intermediate levels optimise tumour growth, and interventions to raise or lower NO(*) concentrations can inhibit it. Concentrations in the high microM range generated by NOS gene therapy or NO(*) donor drugs induce apoptosis in solid tumours in vivo and slow their growth dramatically. These interventions are also potent enhancers of the anticancer effects of cytotoxic chemotherapy, particularly with the anthracyclines and platinum compounds. There is also clear evidence for specificity against malignant compared with normal cells, associated with the specific generation of peroxynitrite. Recent clinical trials have demonstrated both the safety and efficacy of nitric oxide therapy against lung and prostate cancer.