Correlation of chemopreventive efficacy data from the human epidermal cellassay with in vivo data

Continuous exposure to low doses of potentially mutagenic and carcinogenic chemicals over the human lifetime makes the identification of agents, which could reduce the ensuing risk of cancer, beneficial The Human Epidermal Ce ll (HEC) Assay includes multiple exposures to low, non-toxic doses of propa ne sultone, which increases cellular growth and inhibits differentiation, a nd co-exposure to potential chemopreventive agents to determine their abili ty to inhibit the increased growth or increase differentiation. Original da ta are presented on the efficacy of twenty potential cancer chemopreventive agents were screened for efficacy in the HEC Assay. Efficacy was determine d by the ability of agents at nontoxic concentrations, to reverse either of the propane sultone-induced biomarkers, enhanced growth and reduced involu crin expression. Based on the number of positive concentrations and the lac k of toxicity, 1,2-dithiol-3-thione, oltipraz, and a synthetic retinoid Ro 16-9100, were the most active. Eleven of seventeen positive agents were act ive for both endpoints. S-Allylcysteine was only active for the growth inhi bition endpoint, and DFMO, lycopene, perillyl alcohol ursodiol, and black t ea polyphenols were only active for the involucrin endpoint. The three agen ts that have been shown to be negative in animal models, diphenhydramine, d -mannitol, and nordihydroguaiaretic acid, were correctly identified as nega tive by the assay. When the data from previous studies (Elmore et al, Antic ancer Res, 19: 909-918, 1999) are included, a positive response in one or m ore endpoints of the HEC Assay correlates 100% (26/26) with a positive resp onse in one or more of the animal cancer prevention models (8). The availab le data suggest that the HEC Assay response is highly predictive of efficac y in animals in vivo with an overall accuracy of 90%. Future studies will i nclude data with additional negative agents. The con elation of the HEC Ass ay data with data from in vivo studies in animal models, which utilize mult iple carcinogens and multiple target organs, would suggest that this in vit ro assay has the ability to identify agents with the potential to prevent c arcinogen-induced cancer. While our ultimate goal is to identify agents wit h potential efficacy for preventing human cancer, sufficient human data are not yet available to make this correlation.