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 number of men with prostate cancer will not be cured of their disease and will face the possibility of metastatic disease. Thus, development of potent prevention strategies to diminish or eliminate this threat is in order. Cellular exposure to chronic oxidative stress may be 1 possible etiologic factor in the development of many cancers, including prostate cancer. Oxygen radicals can attack DNA directly and result in the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subsequent generation of a range of reactive products that can damage DNA. Disruption of certain genes may result in cellular tolerance to oxidative genomic injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction between 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 damage and/or tolerant to accumulation of oxidized DNA base adducts. These base adducts can be measured by several quantitative methods, such as gas chromatography-mass spectrometry with selected ion monitoring. These sophisticated methods can be readily integrated into prostate cancer chemoprevention studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of these candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational, directed prostate cancer chemoprevention studies to be performed and, together, will help determine the role of chronic oxidative stress in the carcinogenic process of prostate cancer.