Many inorganics are known human carcinogens while others are suspected. Inorganics are very hazardous carcinogens because they are ubiquitous, non-biodegradable, bioaccumulated, and mimic essential elements in biological systems. Exposure to inorganics is inevitable and defining mechanisms is critical in assessing the nature and extent of the human health hazard. Arsenic, cadmium and lead are distinct among metal carcinogens because they do not undergo spontaneous redox reactions and the creation of electrophilic species that directly attack DNA is unlikely. Thus we are actively considering alternative, epigenetic mechanisms. Indirect mechanisms by which metals induce aberrant gene expression and malignant transformation under study include interactions with regulatory proteins, altered DNA methylation status, interactions with DNA polymerase or alterations in receptor mediated processes. Basic aspects of site specific sensitivity are also being explored, and with cadmium poor responsiveness of the metallothionein (MT) gene often dictates susceptibility. Additionally, during arsenic-induced malignant transformation DNA becomes hypomethylated, which in turn facilitates aberrant oncogene activation. This is consistent with the poor mutagenicity of arsenic and provides a basis for the first tenable theory of its mechanism. We also find cadmium will induce tumors of the rat dorsolateral prostate. Prostate cancer is an important and often deadly human malignancy that has often been linked with human exposure to cadmium. Many metals can also have antitumor effects and we also study the antitumor effects of cadmium. This is based on earlier findings that cadmium when used in two stage carcinogenesis model systems causes extensive reductions in spontaneous and nitrosamine-induced liver and lung tumors in mice. New evidence shows cadmium reduces growth and blocks metastasis of human tumor xenografts. The sensitivity of certain tumors, potentially including human tumors, appears to be based in poor expression of the MT gene within the malignancies.
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