MECHANISMS OF PLATINUM-INDUCED MUTAGENESIS

顺式二氨基二氯铂(cis-pt)是最重要的 化疗药物是在过去十年中推出的，是第一个 几个较新的铂(铂)类似物。尽管细胞毒性和诱变性 顺铂的作用是通过形成特定的DNA来实现的 加合物，这些效应背后的分子机制还不是很好 明白了。了解铂的诱变作用将使我们有可能 对铂的作用机制和铂-DNA修复途径有了新的认识。 顺铂及其他铂类似物诱发突变的类型和位置 将会被确认。对突变的比较位点的分析可能 提供对铂试剂形成的加合物的位置的洞察，并可 有助于了解它们的行动机制。 由于未修复的铂加合物对细胞毒性和 致突变性，铂-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 了解铂-DNA修复途径的有效性和保真度。 铂诱导突变“热点”的识别位置将被关联 与抑制DNA复制的铂-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或附近。 铂加合物的位置，也可以识别加合物的形成位置 对铂的致突变性至关重要。 侧翼序列与铂诱导突变的关系， 尤其是对于顺铂诱导的缺失，将被确定。这些 实验可能会开始识别邻近的碱基，这些碱基在 铂诱发突变的产生。 在穿梭载体和整合载体中鉴定铂诱导突变的位置 DNA前病毒将被比对。如果识别到顺式铂诱导的缺失 它将允许进一步的实验，目的是修改这种 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.