CHEMOPREVENTION OF MAMMARY CANCER BY ORGANOSELENIUM

我们一直表明，合成的有机硒化合物(OSC) 是毒性较小的高级癌症化学预防药物 亚硒酸盐，自然产生的硒氨基酸或它们的硫磺类似物。 建议的研究重点是我们的先导化合物[1，4- 并将验证p-xsc是否 或者它的一种代谢物负责化学预防 癌症；此外，它将寻求建立(一)可信的机制(S)，以 这种效果，特别是在启动后阶段 7，12-二甲基苯并(A)菲(DMBA)乳腺肿瘤的致癌作用 以大鼠为模型。我们的初步结果与所获得的结果的比较 以前使用的是苄基硒氰酸酯(BSC)，这让我们相信 谷胱甘肽结合物(BSE-SG)是BSC的一种潜在代谢物，具有较高的 化学预防指数比该DMBA中的母体化合物(BSC) 乳腺肿瘤模型。此外，BSE-SG在pH为2的范围内稳定 37摄氏度时为7.4。这种结合物在体内的疗效 表明全身吸收。然而，这一点还有待确定。 无论是完整的结合物或其代谢物之一被运送到 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偶联物(p-xse-SG)是一个 P-XSC的主要代谢物，将导致芳基的形成 以硒醇中间体为活性化学预防成分。支持 用于形成芳基硒醇中间体的基础是 四硒环芳烃(TSC)的结构鉴定 P-XSC或p-XSE-SG。因此，为了检验我们的假设并实现目标 在本项目中，在目标1中，我们将合成大量的p-xSc，p-xSc XSE-SG和TSC。明确确认p-XSE-SG的存在是一种 P-XSC在体内的初级代谢物，我们将进行合成和 使用双标记版本的p-XSE-SG进行额外的代谢研究。 在目标2中，在确定最大耐受量之后，我们将 比较p-XSC、p-XSE-SG和TSC在起始期和恢复期的疗效 DMBA乳腺肿瘤模型致癌的启动后阶段 在老鼠身上。最有效的化合物将在下面进一步研究 它的延迟管理(DMBA管理后13周)。我们的 到目前为止的结果，加上文献数据，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(COX-2)表达，诱导 细胞凋亡，从而抑制癌症的发生。因此，在目标3中， 我们将研究那些将出现显著影响的OSC 来自目标2的化学预防活性在特别是 在致癌的后起始阶段很重要，即 脂质过氧化(异前列腺素)、环氧合酶-2表达和细胞凋亡等 8-羟基脱氧鸟苷(8-OHdG)水平。本项目的成果 将提供对使用p-XSC和/或以下其中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 并深入到行动的根本机制(S)中。

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.