Most mutagens and many antineoplastic drugs are potent electrophiles. Metallothionein (MT) is though to be one important intracellular protectant against these electrophiles. The sensitivity of organs, such as the prostate, to cadmium carcinogenesis is hypothesized to be due to low basal levels of MT. Induction of MT by pharmacologic and environmental agents can protect cells against electrophilic mutagens, oxidants and antineoplastic drugs. Cells that are resistant to multiple anticancer drugs, including cis diamminedichloroplatinum (II) (CP) and alkylating agents, have been found to overexpress MT but the molecular basis for this overexpression is uncertain. MT has been identified in the nucleus an cytoplasm of normal and malignant cells but the functional significance of differential MT subcellular locations is not yet known. Because gene transfer studies suggest overexpression of human MT ILA alone is insufficient to cause a resistant phenotype to CP or N-methyl-N- nitro-N-nitroguanidine, we hypothesis MT interacts with other cellular elements. The overall goal of this proposal is to define the types of MT in malignant cells, to examine the potential mechanisms by which overexpression of MT leads to resistance to electrophilic agents and to investigate the mechanism(s) responsible for overexpression of MT in CP resistant cells.
Our Specific Aims are: Examine the MT isoform composition in malignant human cells, including prostate cells and CP resistant cells. Determine if MT subcellular location dictates function. Identify and characterize the cellular components with which Mt interacts. Determine CP interactions with DNA and MT in cells with altered levels of MT. Investigate the mechanisms responsible for MT overexpression in CP resistant cells.
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