3. Perspective
Even though mutagenesis by oxygen free radicals has been widely recognized to be a causative factor in the pathogenesis of diseases including cancer, methods for investigating the mechanism for this mutagenesis have not been adequate. Recent advances in molecular biology have allowed one to construct DNA with site-specific modifications identical to those caused by oxygen free radicals and to determine the mutagenic potential of each of these modifications (Basu and Essigman, 1988). Having obtained the spectrum of oxygen free radical mutagenesis. The path is now open to examining different DNA alterations using site-specific mutagenesis. Knowledge of the mutagenic specificity of different lesions produced by oxygen free radicals is critical for determining whether or not the production of oxygen free radicals in cells is a significant factor in spontaneous mutations and carcinogenesis. Of particular interest are mutations in the P53 gene in hepatocellular carcinoma. The prominence of GC→TA substitutions in human tumors (Holstein et al., 1991) is compatible with either aflatoxin- induced DNA damage or with damage by oxygen free radicals. The key question will be whether these mutations are the result of aflatoxin or due to oxygen free radicals generated during chronic inflammation induced by hepatitis virus B or C.
Knowledge of the types of mutations caused by oxygen free radicals in cells could define the contribution of mutagenesis by oxygen free radicals to carcinogenesis. Efforts are required to document mutations produced in shuttle vectors that infect cells and more importantly in specific chromosomal genes. The comparison of the types of mutations produced by oxygen free radicals in the test tube and the types of mutations found in genes associated with malignancy will go a long way in defining the role of oxygen free radicals in he induction of human cancer.
Acknowledgments
This work has been supported by grants from the National Cancer Institute: CA39903 (LAL), and CA08855 (TMR); by a Damon Runyon-Walter Winch ell Cancer Fund Grant: DRG 049 (KCC) and by a training grant from the National Institutes of Health: GM07266 (DF)
