Comparison of experimental and theoretical parameters of the moolgavkar-venzon-knudson incidence function for the stages of initiation and promotion in rat hepatocarcinogenesis

Abstract

Mathematical descriptions of complex biological phenomena, such as cancer, require an experimental format that faithfully recapitulates the biological process. In addition, the biological process must dictate the parameters in the mathematical formula. Evidence from the epidemiology of several human cancers and from experimental carcinogenesis in several organ systems indicates that cancer is a multistage process. The initiation-promotion-progression format of experimental carcinogenesis mimics the development of cancer in humans and other animals. In rats, the altered hepatic focus model of hepatocarcinogenesis has been well characterized and, coupled with the method of quantitative stereology, permits accurate determination of the number and the volume fraction of such altered foci per liver. The placental isozyme of glutathione S-transferase (PGST) is reportedly the best single marker of preneoplasia in the rat liver. Recently, single hepatocytes expressing PGST have been proposed as putatively initiated cells. Quantitation of individual hepatic cells and altered hepatic foci expressing PGST in the livers of rats subjected to an initiation-promotion protocol permits determination of the congruence of the Moolgavkar-Venzon-Knudson (MVK) model with experimental data. The best fit of the MVK model for the preneoplastic stages of hepatocarcinogenesis assumes that all hepatocytes are susceptible and that single hepatocytes expressing PGST are the initiated cell population for the focal lesions that express PGST. Further refinement of the initiation-promotion-progression model to permit accurate quantitation of early malignant conversion should allow a more complete analysis of the congruence of the MVK model for human cancer risk determination. In addition, the MVK model may be extended to other model systems and to human cancers in which early preneoplasia can be quantitated. Furthermore, the use of a more biologically based risk-assessment protocol, such as the MVK model rather than the stochastic one-hit model presently used, would permit incorporation of the present knowledge on the pathogenesis of cancer. To apply experimental data to a mathematical model that reflects the biological processes underlying human cancer development will require integration of the cell kinetics and experimental data to a mathematical model that reflects the biological processes underlying human cancer development including the pharmacokinetic and pharmacodynamic properties of the treatment chemicals.