CANCER PREVENTION BY PROTEASE INHIBITORS

这项赠款提案是对竞争续签 我们的赠款最初是根据RFA第87-CA-15号文件提交的。我们有 建议进行实验以评估蛋白水解酶抑制剂是否为人类 癌症化学预防药物，重点是自然发生的 存在于蔬菜中的蛋白酶抑制剂，如大豆中提取的 Bowman-Birk抑制剂(BBI)和鹰嘴豆抑制剂。活体内 已提议进行致癌研究，以研究阿司匹林的疗效 二甲基肼(DMH)的抗癌蛋白酶抑制活性 诱导大鼠结肠癌的发生。这些研究将在以下情况下进行 大豆来源的BBI及其衍生物(即我们已经 具有体内已知的抗癌活性的药物 或根据我们之前的研究确定的体外实验)。我们已经提出了两项建议 不同方法制备抗癌蛋白水解酶抑制剂 比那些酶抑制剂更好的特性 已经提供给我们；其中包括：1)合成(BBI)的生产 基因产品，经过几次修饰以增加抗癌作用 活性(胰凝乳酶抑制活性)；以及2)修饰 BBI和其他抗癌蛋白酶抑制剂导致 从胃肠道摄取(进入血液和 分布到其他器官部位)。随着新的蛋白水解酶抑制剂 可供我们使用的，我们首先要确定它们的抑制能力 凝乳酶和辐射诱导C3H10T1/2细胞转化。如果 一种化合物具有这些性质，我们将确定其能力：1) 以活跃的形式到达结肠，2)被吸收到血液中， 3)到达胃肠道以外的器官部位。长期的 将进行动物研究，以确定饮食中的蛋白酶 抗癌水平的抑制剂对一般健康有任何影响 动物的生命。在这些研究中，要监测的参数将 包括：动物的生长速度、大体和微观 胰腺的病理改变。这样做的总体目标是 合作项目是生产一种含有膳食的蛋白酶抑制剂 可作为一种无毒的化学预防药物的补充剂 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.