DNA DAMAGE, FREE RADICALS, ORTHO QUINONES AND CANCER

这项建议的主要目的是增加我们对 雌激素致癌作用的潜在机制。 的 自由基物质的产生被认为与 与几种人类病理条件，包括激素 致癌作用和神经元降解，也是 几种外源性物质和代谢抑制剂。 的 实现这一目标的实验方法是可能的， 我们的实验室在分离和稳定 雌酮-3，4-醌（3，4-EQ）和其它邻醌，以及 观察到3，4-EQ诱导单链而非双链DNA 休息. 总的来说，这些发现提供了一个独特的机会， 整合参与这些活动的关键科学人员的专业知识， 为实现以下具体目标， 1. 合成和安全的雌激素邻醌和其他重要化合物 在其结构中具有邻苯二酚/邻醌基团。 2. 表征诱导的DNA损伤的类型、特异性和修复， 用邻醌处理的人类细胞。 3. 阐明细胞生化决定因素介导的代谢 邻醌到DNA破坏物质。 4. 鉴定o-半醌和氧自由基引起o-半醌中DNA损伤 醌处理的人类细胞使用电子自旋共振光谱。

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.