Breast Cancer Chemoprevention Strategies

描述(由申请人提供)：流行病学研究已经确定雌激素水平升高与乳腺癌的发生有关。特别是，天然激素17(3-雌二醇)及其邻苯二酚代谢产物与乳腺癌的发生有关，人们认为雌激素邻苯二酚可引起自由基介导的、直接和/或间接的DNA损伤，这可能导致基因突变，最终导致乳腺癌。我们用新设计的~(32)P-后标记/TLC系统在大鼠乳腺组织和人乳腺组织中检测到几种氧化和其他极性的DMA加合物。与参比氧化加合物的色谱图相似性表明，组织DNA加合物来源于自由基的调节。这些结果表明，这些加合物可能是17-3-雌二醇代谢产物氧化还原循环的结果。我们假设，化学预防药物的组合将比单独使用药物提供更有效的乳腺癌预防。这将通过1)利用具有不同作用模式的药物的组合；以及2)通过使用新的系统性缓释装置来规避毒性来实现。我们通过全身缓释系统给药的鞣花酸干预和饮食干预的初步结果在ACI大鼠模型中引起了相似程度的抑制17-3-雌二醇介导的乳腺肿瘤形成，支持我们的工作假说。一组经验丰富的研究人员将进行以下具体研究，以实现我们的目标：1)确定选定的药物在体内调节雌激素代谢和DNA修复的有效性。2)确定候选药物在体内抑制17-3-雌二醇诱导的细胞增殖的效果。3)确定候选药物抑制17-3-雌二醇诱导的乳腺肿瘤形成的效果，并将雌激素代谢的调节与肿瘤指数相关联。4)确定缓释装置输送的药剂组合是否比单独的药剂更有效地抑制乳腺肿瘤的发生。结果数据将显示，通过不同领域工作的药物组合可以比单独的药物提供更全面的预防乳腺肿瘤，并且全身缓释释放可以通过显著减少有效剂量来规避毒性。这些数据还将确定可以有效预防乳腺癌，或许还有其他荷尔蒙癌症的途径(S)。

DESCRIPTION (provided by applicant): Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular, the natural hormone, 17(3-estradiol and its catechol metabolites have been implicated in breast cancer development, and it is believed that estrogen catechols cause free radical mediated, direct and/or indirect DNA damage, which may lead to gene mutations and ultimately breast cancer. We have detected several oxidative and other polar DMA adducts in the mammary tissue of rats and in human breast tissues by newly devised 32P-postlabeling/TLC systems. Chromatographic similarity with reference oxidative adducts suggests that tissue DNA adducts originated from free radical-mediation. These results suggest that the adducts may have resulted from redox cycling of 17-3-estradiol metabolites. We hypothesize that combination of chemopreventive agents will provide more effective prevention of breast cancer than individual agents. This will be accomplished by 1) utilizing combination of agents with different modes of action; and 2) by using a novel systemic slow-release device to circumvent toxicity. Our preliminary results by interventions with ellagic acid delivered by systemic slow-release system and diet elicited similar degree of inhibition of 17-3-estradiol-mediated mammary tumorigenesis in the ACI rat model, supporting our working hypothesis. A team of experienced investigators will pursue the following specific studies to meet our goals: 1) Determine the efficacy of selected agents to modulate estrogen-metabolism and DNA repair in vivo. 2) Determine the efficacy of candidate agents to diminish 17-3-estradiol-induced cell proliferation in vivo. 3) Determine the efficacy of candidate agents to inhibit 17-3-estradiol-induced mammary tumorigenesis, and correlate modulation of estrogen metabolism with tumor indices. 4) Determine if combination of agents delivered by the slow-release device will provide more effective inhibition of mammary tumorigenesis compared with the individual agents. The resulting data will reveal that combination of agents working via different arenas can provide more complete prevention of mammary tumors than individual agents, and that the systemic slow-release delivery can circumvent toxicity by significantly reducing the effective dose. The data will also identify pathway(s) that can be targeted for effective prevention of breast cancer, and perhaps other hormonal cancers.