Colon and liver anticarcinogenicity by acetaminophen

描述(由申请人提供)： 这项拟议研究的总体目标是检验这样一种假设，即酚类化合物可以通过阻断作为活性亲电剂的致癌物的细胞效应，在低水平上起到抗癌作用。为了验证这一假设，我们将在使用广泛使用的止痛药对乙酰氨基酚(APAP)的大鼠身上进行一系列体内研究，该药已显示出在结肠中的抗癌特性。作为大鼠模型致癌物，3，2‘-二甲基-4-氨基联苯(DMAB)和2-氨基-3-甲基-3-咪唑并[4，5-f]喹啉(IQ)将用于在大鼠结肠和肝脏产生中等水平的起始致癌物。我们将建立低水平的APAP抑制早期致癌物诱导的效应的能力，这些效应是启动结肠癌和肝癌发生的基础，例如促进细胞增殖、减少细胞凋亡和诱导癌前病变，并将研究这种抑制的机制(S)，重点是阻断致癌物的细胞内反应性(即加合物形成)。这些实验将在以下三个具体目标中进行：1.确定低剂量的致癌物3，2‘-二甲基-4-氨基联苯(DMAB)和2-氨基-3-甲基-3-咪唑[4，5-f]喹啉(IQ)在大鼠结肠和肝脏产生中等水平的起始作用，以研究低水平的APAP对其抑制作用；2.建立低水平APAP抑制致癌物启动的剂量效应，以确定机制研究的条件；3.确定低水平APAP是否通过减少IQ DNA加合物的形成来抑制致癌物的启动，以深入了解潜在的抗癌机制。这些实验将为未来预防人类致癌物质(如黄曲霉毒素B1)的研究提供基础。此外，这些实验将为使用APAP降低癌症风险的流行病学观察提供支持。

DESCRIPTION (provided by applicant): The overall objective of the proposed research is to examine the hypothesis that phenolic compounds can act as anticarcinogens at low levels by blocking the cellular effects of carcinogens that operate as reactive electrophiles. In testing this hypothesis, we will conduct a series of in vivo studies in rats with the widely used analgesic acetaminophen (APAP), which has demonstrated anticarcinogenic properties in colon. As model carcinogens in the rat, 3,2'-dimethyl-4-aminobiphenyl (DMAB) and 2-amino-3-methyl-3H-imidazo [4,5-f]quinoline (IQ) will be used to produce a moderate level of initiation in rat colon as well as liver. We will establish the ability of low levels of APAP to inhibit the early carcinogen-induced effects that underlie initiation of colon and liver carcinogenesis, such as enhanced cell proliferation, decreased apoptosis and induction of preneoplastic lesions, and will study the mechanism(s) of this inhibition, focusing on blocking of intracellular reactivity of the carcinogens (i.e., adduct formation). These experiments will be pursued in three specific aims as follows: 1. Define low doses of the carcinogens 3,2'-dimethyl-4-aminobiphenyl (DMAB) and 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) that produce a moderate level of initiation in rat colon and liver to be studied for inhibition by low levels of APAP; 2. Establish the dose responses for inhibition of carcinogen-induced initiation by low levels of APAP against selected doses of carcinogens in order to determine conditions for mechanistic studies and 3. Determine whether low levels of APAP inhibit initiation by reduction of formation of IQ DNA adducts in order to gain insight into potential mechanisms of anticarcinogenicity. These experiments will provide the basis for future studies of prophylaxis against human carcinogens, such as aflatoxin B1. In addition, these experiments will provide support for the epidemiological observations of reduced cancer risk associated with the use of APAP.