MECHANISMS OF PLATINUM-INDUCED MUTAGENESIS

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Cis-diamminodichloroplatinum (cis-Pt) is one of the most important chemotherapeutic agents introduced in the last decade and is the first of several newer platinum (Pt) analogs. Although the cytotoxic and mutagenic effects of cis-Pt are mediated through the formation of specific DNA adducts, the molecular mechanisms underlying these effects are not well understood. Understanding Pt-induced mutagenesis will make it possible to obtain new insights on Pt's mechanism of action and Pt-DNA repair pathways. The type and location of mutations induced by cis-Pt and other Pt analogs will be identified. Analysis of the comparative sites of mutation may provide insights into the location of adducts formed by Pt agents and may contribute to an understanding of their mechanism of action. Since unrepaired platinum adducts contribute to cytotoxicity and mutagenicity, the effect of Pt-DNA repair modulation will be studied in repair deficient cells. These studies will contribute to a better understanding of the effectiveness and fidelity of Pt-DNA repair pathway. Identified sites of Pt-induced mutational "hot spots" will be correlated with the location of Pt-DNA adducts that inhibit DNA replication. These experiments will aid in determining if mutational sites occur at or near the sites of Pt adducts and may also identify sites of adduct formation critical for Pt-induced mutagenicity. The relationship between flanking sequences and Pt-induced mutations, especially for a cis-Pt induced deletion, will be determined. These experiments may begin to identify neighboring bases important in the generation of Pt-induced mutations. Identified sites of Pt-induced mutation in a shuttle vector and integrated DNA provirus will be compared. If a cis-Pt induced deletion is identified it will allow further experiments aimed at modifying the generation of this deletion.