DNA DAMAGE, FREE RADICALS, ORTHO QUINONES AND CANCER

这项建议的主要目的是增进我们对 雌激素致癌的潜在机制(S)。这个 自由基物种的产生被认为与 人类的几种病理情况，包括荷尔蒙 致癌和神经元退化，也是 几种外源物质和抗肿瘤药物的代谢。这个 实现这一目标的实验方法是由于最近的 我们实验室在分离和稳定病毒方面取得的成功 雌酮-3，4-苯二酚(3，4-EQ)和其他邻苯二酚，以及 3，4-EQ诱导单链DNA而不是双链DNA的观察 休息一下。总体而言，这些发现提供了一个独特的机会 整合参与这些项目的关键科学人员的专业知识 努力实现以下具体目标： 1.雌激素邻苯二酚等重要化合物的合成及安全性 在其结构中具有邻苯二酚/邻苯二酚基团。 2.确定小鼠脑内DNA损伤的类型、特异性和修复 用邻苯二酚处理的人体细胞。 3.阐明细胞生化决定因素对代谢的调节作用 邻苯二酚类化合物对DNA具有破坏作用。 4.鉴定O-半喹酮类化合物和氧自由基对O-半喹酮和氧自由基的DNA损伤作用 用电子自旋共振波谱研究苯醌处理的人体细胞。

The major goal of this proposal is to increase our understanding of the underlying mechanism(s) involved in estrogen carcinogenesis. The production of free radical species has been postulated to be associated with several human pathological conditions, including hormonal carcinogenesis and neuronal degradation, and is also the consequence of metabolism of several xenobiotics and antineoplastic agents. The experimental approach to attain this goal is made possible by the recent successes in our laboratories in the isolation and stabilization of estrone-3, 4-quinone (3,4-EQ) and other ortho-quinones, as well as the observation that 3,4-EQ induces single strand- but not double-strand DNA breaks. Collectively, these findings present a unique opportunity to integrate the expertise of the key scientific personnel involved in these diverse areas in an effort to achieve the following specific objectives: 1. Synthesize and secure estrogen o-quinones and other important compounds having the catechol/o-quinone group in their structure. 2. Characterize the type, specificity and repair of DNA damage induced in human cells treated with o-quinones. 3. Elucidate cellular biochemical determinants mediating the metabolism of o-quinones to DNA damaging species. 4. Identify o-semiquinones and oxyradicals eliciting DNA damage in o- quinone-treated human cells using electron spin resonance spectroscopy.