CHEMOPREVENTION OF MAMMARY CANCER BY ORGANOSELENIUM

我们一直表明，合成有机硒化合物（OSC） 是上级癌症化学预防剂， 亚硒酸盐、天然存在的硒代氨基酸或它们的硫类似物。 拟议的研究重点是我们的铅化合物[1，4- 亚苯基双（亚甲基）硒氰酸酯，p-XSC]，并将验证p-XSC是否 或其代谢物之一负责化学预防 癌症;此外，它将寻求建立（一个）合理的机制， 这种影响，特别是在启动后阶段， 7，12-二甲基苯并蒽（DMBA）乳腺肿瘤的致癌作用 大鼠模型。我们的初步结果与那些得到的比较 以前与苄基硒氰酸酯（BSC），使我们相信， 谷胱甘肽结合物（BSe-SG）是BSC的一种假定代谢产物， 化学预防指数比母体化合物（BSC）在这个DMBA 乳腺肿瘤模型此外，BSe-SG在pH 2 在37摄氏度时是7.4该缀合物在体内的功效 表明全身吸收。然而， 无论是完整的缀合物还是其代谢物之一被递送至 肝外组织然而，我们未来的研究将集中在p-XSC上， 因为我们假设谷胱甘肽结合物（p-XSe-SG）是一种 p-XSC的初级代谢产物，这将导致形成芳基 硒醇中间体作为活性化学预防成分。支持 用于形成芳基硒醇中间体的方法是基于 鉴定四硒环吩（TSC）为源自 p-XSC或p-XSe-SG。因此，为了验证我们的假设并实现目标， 在本项目的目标1中，我们将合成大量的p-XSC，p- XSe-SG和TSC。为了明确地证实p-XSe-SG的存在， 在体内p-XSC的主要代谢产物，我们将进行合成， 用双标记形式的p-XSe-SG进行额外的代谢研究。 在目标2中，在确定最大耐受剂量后，我们将 比较p-XSC、p-XSe-SG和TSC在启动和 在DMBA乳腺肿瘤模型中的癌发生的后起始阶段 对大鼠最有效的化合物将进一步检查以下 延迟给药（DMBA给药后13周）。我们 迄今为止的结果，连同文献数据，似乎有利于 假设p-XSC和/或其代谢物之一可以抑制 氧化损伤，下调环氧合酶（考克斯-2）表达，诱导 细胞凋亡，并因此抑制癌发生。因此，在目标3中， 我们将研究那些将出现重大影响的OSC的影响， Aim 2对标记物的化学预防活性， 重要的是在后启动阶段的致癌作用，即水平 脂质过氧化（异前列腺素）、考克斯-2表达和细胞凋亡， 8-羟基脱氧鸟苷（8-OHdG）水平。该项目的结果 将提供使用p-XSC和/或以下之一的可行性的见解 其代谢产物在未来乳腺癌化学预防临床试验中的应用 并深入研究潜在的作用机制。

We have consistently shown that synthetic organoselenium compounds (OSC) are superior cancer chemopreventative agents with less toxicity than selenite, naturally-occurring selenoamino acids, or their sulfur analogs. The proposed research focuses on our lead compound [1, 4- phenylenebis(methylene)selenocyanate, p-XSC] and will verify whether p-XSC or one of its metabolites is responsible for the chemoprevention of cancer; moreover it will seek to establish (a) plausible mechanism(s) for such an effect, especially during the post-initiation phase of carcinogenesis in the 7, 12-dimethylbenz(a)anthracene (DMBA) mammary tumor model in rats. Comparisons of our preliminary results with those obtained previously with benzyl selenocyanate (BSC), lead us to believe that glutathione conjugate (BSe-SG), a putative metabolite of BSC, has a higher chemopreventative index than the parent compound (BSC) in this DMBA mammary tumor model. In addition, BSe-SG is stable at pH ranges between 2 and 7.4 at 37 degrees Celsius. The efficacy of this conjugate in vivo indicates systemic absorption. However, it remains to be determined whether the intact conjugate or one of its metabolites is delivered to extrahepatic tissues. Our future studies, however, will focus on p-XSC, because we hypothesize that the glutathione conjugate (p-XSe-SG) is a primary metabolite of p-XSC, that will lead to the formation of an aryl selenol intermediate as the active chemopreventative principle. Support for the formation of an aryl selenol intermediate is based on the identification of tetraselenocyclophane (TSC) as a metabolite derived from p-XSC or p-XSe-SG. Thus, to test our hypothesis and to achieve the goals of this Project, in Aim 1, we will synthesize ample materials of p-XSC, p- XSe-SG, and TSC. To unequivocally confirm the presence of p-XSe-SG as a primary metabolite of p-XSC in vivo, we will conduct the synthesis and additional metabolism studies with the dual-labelled version of p-XSe-SG. In Aim 2, following determination of maximally tolerated doses, we will compare the efficacy of p-XSC, p-XSe-SG, and TSC in the initiation and post-initiation phases of carcinogenesis in the DMBA mammary tumor model in rats. The most effective compound will be further examined following its delayed administration (13 weeks after DMBA administration). Our results to date, together with literature data, appear to favor the hypothesis that p-XSC and/or one of its metabolites could inhibit oxidative damage, down-regulate cyclooxygenase (COX-2) expression, induce apoptosis and, consequently, inhibit carcinogenesis. Therefore, in Aim 3, we will examine the effect of those OSC that will emerge with significant chemopreventative activity from Aim 2 on markers that are especially important in the post-initiation phase of carcinogenesis, namely levels of lipid peroxidation (isoprostane), COX-2 expression, and apoptosis and on levels of 8-hydroxydeoxy-guanosine (8-OHdG). The results of this Project will provide insights into the feasibility of using p-XSC and/or one of its metabolites in future clinical trials on breast cancer chemoprevention and into the underlying mechanism(s) of action.