Colon and liver anticarcinogenicity by acetaminophen

描述（由申请人提供）： 拟议研究的总体目标是检验酚类化合物可以通过阻断作为反应性亲电体的致癌物的细胞效应而在低水平下作为抗癌剂的假设。为了验证这一假设，我们将在大鼠体内进行一系列广泛使用的止痛剂对乙酰氨基酚（APAP）的体内研究，该药物已被证明具有结肠抗癌特性。作为大鼠模型致癌物，将使用3，2 '-二甲基-4-氨基联苯（DMAB）和2-氨基-3-甲基-3H-咪唑并[4，5-f]喹啉（IQ）在大鼠结肠和肝脏中产生中等水平的起始作用。我们将建立低水平APAP抑制早期致癌物诱导效应的能力，这些效应是结肠和肝脏致癌作用的基础，例如细胞增殖增强、细胞凋亡减少和癌前病变的诱导，并将研究这种抑制的机制，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进行：1。定义低剂量的致癌物3，2 '-二甲基-4-氨基联苯（DMAB）和2-氨基-3-甲基-3H-咪唑并[4，5-f]喹啉（IQ），其在大鼠结肠和肝脏中产生中等水平的起始，以研究低水平的APAP的抑制作用; 2.建立剂量反应抑制致癌物诱导的启动低水平的APAP对选定剂量的致癌物，以确定条件的机制研究和3。确定低水平的APAP是否通过减少IQ DNA加合物的形成来抑制启动，以深入了解潜在的抗癌机制。这些实验将为今后预防人类致癌物如黄曲霉毒素B1的研究提供基础。此外，这些实验将为流行病学观察提供支持，即与使用APAP相关的癌症风险降低。

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.