XENOBIOTICS, INFLAMMATION AND CARCINOGENESIS

Summary

Principal Investigator: James Lewis
Abstract: Many xenobiotics are immunotoxicologic by aberrantly stimulating the immune system inducing damage in the host. The association between chemicals, carcinogenesis and inflammation has long been noted. Phorbol esters have been shown to be both the inflammatory agents and the tumor promoting agents in the vesicant croton oil. Based on earlier studies showing that phorbol esters induce the release of genotoxic oxygen radicals from inflammatory cells, and most inhibitors of promotion by phorbol esters are antiinflammatory agents or antioxidants, it has been hypothesized that, in addition to their direct effects on target cells, phorbol esters may also work by indirectly inducing DNA damage in target cell through their effects on inflammatory cells. We and others have shown that inflammatory cells exposed to phorbol esters can induce DNA damage in themselves and surrounding cells. We have shown that SENCAR mice, which have been bred for their sensitivity to phorbol ester promotion have the following enhanced responses to phorbol esters over C57B1/6 mice which are resistant: 1) a more intense inflammatory response in skin, 2) macrophages from SENCAR mice release more oxidants, and 3) macrophages from SENCAR mice induce more DNA damage in surrounding cells. Furthermore we have preliminary data suggesting that levels of protein kinase C (PKC), which phorbol esters bind to and activate, may be elevated in SENCAR mice. Thus, we propose the following hypothesis: Responses of SENCAR mice to phorbol esters are generally elevated of those of C57BL/6 mice, PKC may be a central molecular mechanism mediating enhanced sensitivity of SENCAR mice to phorbol esters, that one result of this is increased inflammation, oxidant release, and DNA damage. We propose to test this hypothesis by determining if enhanced responses to phorbol esters by SENCAR mice occurs in a wide range of cells, if there are differences in PKC between the strains, if enhanced inflammation segregates with enhanced tumor promotion in cross breeding experiments, if sensitivity to phorbol esters is under single or multigene control, and if enhanced release of oxidants by inflammatory cells results in enhanced DNA damage.
Funding Period: 1987-05-01 - 1992-04-30
more information: NIH RePORT