MECHANISMS OF PLATINUM-INDUCED MUTAGENESIS

顺式二氨基二氯铂（cis-Pt）是一种重要的 在过去的十年中引入的化疗药物，是第一个 几种较新的铂（Pt）类似物。 虽然细胞毒性和致突变性 顺式铂的作用是通过形成特异性DNA来介导的 加合物，这些影响的分子机制是不是很好 明白 了解Pt诱导的诱变将使我们有可能 获得关于Pt的作用机制和Pt-DNA修复途径的新见解。 顺式铂和其他铂类似物诱导突变的类型和位置 将被识别。 比较突变位点的分析可能 提供了对铂试剂形成的加合物位置的深入了解， 有助于了解其作用机制。 由于未修复的铂加合物导致细胞毒性， 致突变性，Pt-DNA修复调节的影响将在 修复缺陷细胞。 这些研究将有助于更好地 理解Pt-DNA修复途径的有效性和保真度。 确定的Pt诱导突变“热点”位点将与 与抑制DNA复制的Pt-DNA加合物的位置有关。 这些 实验将有助于确定突变位点是否发生在 铂加合物的位点，也可以确定加合物形成的位点 对Pt诱导的致突变性至关重要。 侧翼序列与Pt诱导突变之间的关系， 特别是对于顺式-Pt诱导的缺失。 这些 实验可以开始以鉴定在所述细胞中重要的相邻碱基 产生Pt诱导的突变。 鉴定穿梭载体中Pt诱导突变的位点，并整合 将比较DNA前病毒。 如果鉴定出顺式Pt诱导的缺失 它将允许进一步的实验，旨在修改这一产生， 删除。

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.