There is considerable epidemiological evidence showing inverse correlations between intake of fruits and vegetables and the incidence of certain cancers including lung, colon and prostate. Previous clinical trials have focused on beta-carotene as the active anticancer agent, but results of these trials were negative and other carotenoids are now being considered. One of these is lycopene. There is experimental and epidemiological evidence suggesting that lycopene has a protective effect against certain cancers, but it is limited. Also, recent recommendations on cancer chemoprevention have shifted from the use of single agents to mixtures. Therefore, lycopene-rich mixtures from natural sources represent one potential chemopreventative mix. Another potential anticancer agent for which there is some epidemiological, clinical and experimental support is selenium. Experimental evidence for protective effects and for a mechanism of protection are important in establishing these agents as chemopreventatives. This proposal addresses both the effectiveness and the mechanism of protection by a lycopene-rich mixture, and organic selenium with and without added tocopherols mixture, against spontaneous and carcinogen-induced mutagenesis in lac transgenic mice and rats in lung, colon, prostate and kidney. Three different types of carcinogens will be employed: the procarcinogen, benzo(a)pyrene, the direct-acting methylating agent, N- methyl-N-nitrosourea, and the oxidative agent ferric-nitriloacetate. The assay is relatively rapid (compared to most carcinogenesis assays) and utilizes small numbers of animals. as many genotoxic carcinogens induce oxidative damage in addition to alkylation, and such oxidative damage may play a role in initiation and promotion, antioxidant inhibitors such as those here, may act on different stages of carcinogenesis (the formation of DNA damage, and/or the replication- dependent conversion of damage to mutations). Thus, inhibitors will be administered at different times relative to carcinogens to determine which stage of the mutagenesis process is inhibited. Tissue and blood levels of inhibitors will also be determined.
|Guttenplan, Joseph B; Khmelnitsky, Michael; Haesevoets, Roderick et al. (2004) Mutational spectrum of bleomycin in lacZ mouse kidney: a possible model for mutational spectrum of reactive oxygen species. Mutat Res 554:185-92|
|Kosinska, Wieslawa; Pelle, Edward; von Pressentin, Marcia d M et al. (2002) Comparative mutagenicities of bleomycin and ferric-nitrilotriacetate in lacZ mice. Cancer Lett 187:41-6|
|Guttenplan, J B; Chen, M; Kosinska, W et al. (2001) Effects of a lycopene-rich diet on spontaneous and benzo[a]pyrene-induced mutagenesis in prostate, colon and lungs of the lacZ mouse. Cancer Lett 164:1-6|
|Kosinska, W; von Pressentin, M D; Guttenplan, J B (1999) Mutagenesis induced by benzo[a]pyrene in lacZ mouse mammary and oral tissues: comparisons with mutagenesis in other organs and relationships to previous carcinogenicity assays. Carcinogenesis 20:1103-6|