CANCER PREVENTION BY PROTEASE INHIBITORS

这项赠款建议是第二次修订的竞争性更新， 我们最初提交的赠款是为了回应RFA No.87-CA-15。 我们有 建议的实验，以评估蛋白酶抑制剂作为可能的人类 癌症化学预防剂，重点是自然发生的 蛋白酶抑制剂存在于蔬菜如大豆衍生的 Bowman-Birk抑制剂（BBI）和鹰嘴豆抑制剂。 体内 已经提出了致癌研究来研究 二甲肼抗癌蛋白酶抑制剂活性 诱发大鼠结肠癌。 这些研究将与 大豆衍生的BBI及其衍生物（即，这些化合物我们已经 我们可以得到已知具有体内抗癌活性的化合物 或如我们先前的研究所确定的体外）。 我们提出了两个 生产抗癌蛋白酶抑制剂的不同方法， 比那些蛋白酶抑制剂中存在的那些更好的特性 我们已经可以使用;这些包括：1）合成（BBI） 基因产物，有几个修改，以增加抗癌 活性（胰凝乳蛋白酶抑制活性）;和2）修饰 BBI和其他抗癌蛋白酶抑制剂导致增加 从胃肠道摄取（进入血流， 分布到其他器官部位）。 随着新的蛋白酶抑制剂成为 提供给我们使用，我们将首先确定其抑制能力， 糜蛋白酶和辐射诱导的转化在C3H10T1/2细胞中。 如果 一个化合物具有这些特性，我们将确定它的能力：1） 以活性形式到达结肠，和2）被吸收到血流中， 和3）到达胃肠道外的器官部位。 长期 将进行动物研究以确定膳食蛋白酶是否 抗癌水平的抑制剂对一般健康有任何影响 动物们。 在这些研究中，监测的参数将 包括：动物的生长速度， 胰腺的病理变化。 其总体目标是 合作项目是生产一种蛋白酶抑制剂， 可作为无毒化学预防剂， 人类癌症

This grant proposal is the second revision of the competitive renewal of our grant originally submitted in response to RFA No. 87-CA-15. We have proposed experiments to evaluate protease inhibitors as possible human cancer chemopreventive agents, with emphasis on the naturally occurring protease inhibitors present in vegetables such as the soybean derived Bowman-Birk Inhibitor (BBI) and the chick pea inhibitor. In vivo carcinogenesis studies have been proposed to study the efficacy of anticarcinogenic protease inhibitor activity on dimethylhydrazine (DMH) induced colon carcinogenesis in rats. These studies will be performed with soybean-derived BBI and its derivatives (i.e., those compounds we already have available to us which contain known anticarcinogenic activity in vivo or in vitro as determined from our previous studies). We have proposed two different ways to produce anticarcinogenic protease inhibitors with characteristics better than those which exist in those protease inhibitors already available to us; these include: 1) production of synthesized (BBI) gene products, with several modifications to increase the anticarcinogenic activity (the chymotrypsin inhibitory activity); and 2) modifications of BBI and other anticarcinogenic protease inhibitors to result in an increase in uptake from the gastrointestinal tract (into the bloodstream and distribution to other organ sites). As new protease inhibitors become available to us for use, we will first determine their ability to inhibit chymotrypsin and radiation induced transformation in C3H10T1/2 cells. If a compound has these properties, we will determine its ability to: 1) reach the colon in an active form, and 2) be taken up into the bloodstream, and 3) reach organ sites outside the gastrointestinal tract. Long-term animal studies will be performed to determine whether dietary protease inhibitors at anticarcinogenic levels have any effect on the general health of the animals. In these studies, the parameters to be monitored will include: the growth rate of the animals and gross and microscopic pathological changes in the pancreas. The overall aim of this collaborative project is to produce a protease inhibitor containing dietary supplement which can function as a non-toxic chemopreventive agent for human cancer.