COMPARISON OF EXPERIMENTAL AND THEORETICAL PARAMETERS OF THE MOOLGAVKAR-VENZON-KNUDSON INCIDENCE FUNCTION FOR THE STAGES OF INITIATION AND PROMOTION IN RAT HEPATOCARCINOGENESIS

Mathematical descriptions of complex biological phenomena, such as can cer, require an experimental format that faithfully recapitulates the biological process. In addition, the biological process must dictate t he parameters in the mathematical formula. Evidence from the epidemiol ogy of several human cancers and from experimental carcinogenesis in s everal organ systems indicates that cancer is a multistage process. Th e initiation-promotion-progression format of experimental carcinogenes is mimics the development of cancer in humans and other animals. In ra ts, the altered hepatic focus model of hepatocarcinogenesis has been w ell characterized and, coupled with the method of quantitative stereol ogy, permits accurate determination of the number and the volume fract ion of such altered foci per liver. The placental isozyme of glutathio ne S-transferase (PGST) is reportedly the best single marker of preneo plasia in the rat liver. Recently, single hepatocytes expressing PGST have been proposed as putatively initiated cells. Quantitation of indi vidual hepatic cells and altered hepatic foci expressing PGST in the l ivers of rats subjected to an initiation-promotion protocol permits de termination of the congruence of the Moolgavkar-Venzon-Knudson (MVK) m odel with experimental data. The best fit of the MVK model for the pre neoplastic stages of hepatocarcinogenesis assumes that all hepatocytes are susceptible and that single hepatocytes expressing PGST are the i nitiated cell population for the focal lesions that express PGST. Furt her refinement of the initiation-promotion-progression model to permit accurate quantitation of early malignant conversion should allow a mo re complete analysis of the congruence of the MVK model for human canc er risk determination. In addition, the MVK model may be extended to o ther model systems and to human cancers in which early preneoplasia ca n be quantitated. Furthermore, the use of a more biologically based ri sk-assessment protocol, such as the MVK model rather than the stochast ic one-hit model presently used, would permit incorporation of the pre sent knowledge on the pathogenesis of cancer. To apply experimental da ta to a mathematical model that reflects the biological processes unde rlying human cancer development will require integration of the cell k inetics and experimental data to a mathematical model that reflects th e biological processes underlying human cancer development including t he pharmacokinetic and pharmacodynamic properties of the treatment che micals.