G-ACTIN AS A RISK FACTOR AND MODULATABLE END-POINT FOR CANCER CHEMOPREVENTION TRIALS

Because tumorigenesis is an ongoing process, biomarkers can be used to identify individuals at risk for bladder cancer, and treatment of tho se at risk to prevent or slow further progression could be an effectiv e means of cancer control given accurate individual risk assessment. T umorigenesis proceeds through a series of defined phenotypic changes, including those in genetically altered cells destined to become cancer as well as in surrounding normal cells responding to the altered cyto kine environment. A panel of biomarkers for the changes can provide a useful system for individual risk assessment in cancer patients and in individuals exposed to carcinogens. The use of such markers can incre ase the specificity of chemoprevention trials by targeting therapy to patients likely to respond, and thereby markedly reduce the costs of t he trials. Previous studies in our laboratories showed the cytoskeleta l proteins G- and F-actin reflect differentiation-reldted changes in c ells undergoing tumorigenesis and in adjacent ''field'' cells, and a p attern of low F-actin and high G-actin is indicative of increased risk . Actin changes may be a common feature in genetic and epigenetic carc inogenic mechanisms. In a group of over 1600 workers exposed to benzid ine, G-actin correlated with exposure, establishing it as an early mar ker of effect. In another study, a profile of biomarkers was monitored in patients who underwent transurethral resection of bladder tumor (T URBT) and received Bacillus Calmette Guerin (BCC) and/or DMSO. The pri mary objective was to determine how the defined biomarkers expressed i n the tumor and the field correlate with clinical response and recurre nce. DMSO, known to modulate C-actin in vitro, was used as an agent. R esults strongly support the hypothesis that cytosolic C-actin levels m easured by quantitative fluorescence image analysis (QFIA) can be an i mportant intermediate endpoint marker for chemoprevention and that the p300 (M344) and DNA ploidy markers identify a high-risk group that re quires more aggressive therapy and recurrence monitoring. Further rese arch with other markers has shown that DD23 and nuclear actin, both of wh ich identify late, specific changes, may increase the battery of u seful markers. Taken together these studies show how biomarkers are em ployed to study individuals at risk, aid in the selection of chemoprev entive compounds and assist in the understanding of the pathogenesis o f malignancy. (C) 1997 Wiley-Liss, Inc.