OXIDATIVE DNA DAMAGE AND HEPATITIS B VIRUS ONCOGENESIS

这个提议的目的是测试氧化DNA的假设

The purpose of this proposal is to test the hypothesis that OXIDATIVE DNA DAMAGE PLAYS A ROLE IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA SECONDARY TO HEPATITIS B VIRUS (HBV HCC) IN MAN. We postulate that HBV HCC will contain increased amounts of the DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OH-dG), which is a marker of this type of damage. To test this hypothesis, the following studies will be done on patients undergoing martial hepatic resection for HBV HCC: medical history; serum viral markers for HBV and for Hepatitis C; serum alpha feto-protein, a relatively insensitive marker of HCC; and analysis of 8- OH-dG in liver (tumor and peri-tumoral tissue). "Tumor control" groups (patients with HBV negative HCC and with extrahepatic tumor metastatic to liver undergoing partial hepatic resection) will be studied in similar fashion as will "disease control" patients with endstage alcoholic liver disease (ALD) undergoing liver transplantation (LT). Ten-fifteen patients per group per year will be studied, consistent with the previous experience at our institution with the diagnosis of HBV HCC. We also propose that urinary 8-OH-dG will be a useful marker of hepatic 8- OH-dG. Thus hepatic 8-OH-dG values from the above patients will be correlated with urinary 8-OH-dG in two urine samples obtained in the preoperative period and in urine obtained intraoperatively. Urine samples obtained from healthy volunteers who are age- and sex-matched to the HBV HCC patients, will also be analyzed for 8-OH-dG. Pilot studies in the healthy control group will examine intra-individual variation and the effect of fasting on urinary 8-OH-dG. Since the anhepatic phase of the LT procedure offers a unique opportunity to investigate the contribution of hepatic 8-OH-dG to urinary 8-OH-dG, the latter will be measured during LT: before, during, and following the anhepatic phase. The combination of carefully selected clinical groups and state-of the art technology for 8-OH-dG represent an excellent means of testing new hypothesis of HBV carcinogenesis which could lead the way to improve screening, therapy, and ultimately, prevention of HBV HCC.