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.
| Williams, Gary M; Iatropoulos, Michael J; Jeffrey, Alan M et al. (2007) Inhibition by acetaminophen of neoplastic initiation elicited in rat liver by the DNA-reactive hepatocarcinogen N-acetyl-2-aminofluorene. Eur J Cancer Prev 16:528-34 |
