ROLE OF CATECHOL FORMATION IN ESTROGEN-MEDIATED CANCER

非蛋白结合雌二醇与乳腺癌发病关系的流行病学研究 乳腺癌患者血清中的水平提供了 我们对生物学形成的基本研究的基本原理 雌激素介导的癌症中雌二醇的活化代谢物。 乳腺 癌症被认为是尿道介导的，雌激素被认为是 是肿瘤表达的主要媒介。 本研究的目的 计划是建立儿茶酚雌激素形成的作用， 雌激素介导的癌症 我们的假设是致癌物质 雌激素的潜力将与它们的代谢率相关， 激活儿茶酚，但不会与他们的激素 活动 对这一假设的支持是提供了结果， Balb/c 3 T3细胞亚克隆的体外肿瘤转化和来自 叙利亚仓鼠肝细胞致癌性的体内试验。 一 四种结构上相关的化合物，由两个分子组成 活性雌激素和两种非生殖活性衍生物将提供 支持我们中心假设的证据 的显著贡献 这项计划将是发现一种具有生物活性的非致癌物质， 雌激素. 如果我们的体外实验结果得到了体内证据的支持， 体内模型系统，它将提供一个可疑的机制确认 参与与内源性非蛋白结合相关的致癌作用 血清雌二醇水平和治疗性雌激素的作用。

Epidemiological studies on the association of nonprotein-bound estradiol levels in serum from women who developed breast cancer provide the rationale for our basic investigation of the formation of biologically activated metabolites of estradiol in estrogen-mediated cancer. breast cancer is considered to be hormonally mediated, and estrogens are believed to be the prime agents in tumor expression. The objective of this research program is to establish the role of catechol estrogen formation in estrogen-mediated cancer. Our working hypothesis is that the carcinogenic potential of estrogens will correlate with their rates of metabolic activation to catechols, but will not be related to their hormonal activity. Support for this hypothesis is provided by results from the in vitro neoplastic transformation of a subclone of Balb/c 3T3 cells and from an in vivo assay for hepatocellular carcinogenicity in Syrian hamsters. A group of four structurally related compounds composed of two hormonally active estrogens and two hormonally inactive derivatives will provide evidence to support our central hypothesis. A significant contribution of this program will be the discovery of a hormonally active noncarcinogenic estrogen. If our in vitro results are supported by evidence from the in vivo model system, it will provide confirmation of a suspected mechanism involved in carcinogenesis associated with endogenous nonprotein bound serum estradiol levels and the effects of therapeutic estrogens.