Oxidative stress in chemoprevention trials

Prostate cancer continues to be the most frequently diagnosed cancer in men in the United States. Despite aggressive intervention, a significant numbe r of men with prostate cancer will not be cured of their disease and will f ace the possibility of metastatic disease. Thus, development of potent prev ention strategies to diminish or eliminate this threat is in order. Cellula r exposure to chronic oxidative stress may be 1 possible etiologic factor i n the development of many cancers, including prostate cancer. Oxygen radica ls can attack DNA directly and result in the accumulation of potentially pr omutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subse quent generation of a range of reactive products that can damage DNA. Disru ption of certain genes may result in cellular tolerance to oxidative genomi c injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction b etween potentially damaging electrophiles and glutathione. inactivation of GSTP1 has been documented to occur in nearly 100% of human prostate cancers ; it is also frequently inactivated in prostatic intraepithelial neoplasia lesions. This inactivation may leave the cell vulnerable to oxidative DNA d amage and/or tolerant to accumulation of oxidized DNA base adducts, These b ase adducts can be measured by several quantitative methods, such as gas ch romatography-mass spectrometry with selected ion monitoring. These sophisti cated methods can be readily integrated into prostate cancer chemopreventio n studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of thes e candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational. di rected prostate cancer chemoprevention studies to be performed and, togethe r, will help determine the role of chronic oxidative stress in the carcinog enic process of prostate cancer. (C) 2001, Elsevier Science Inc.