11. Cancer Prevention Division
Research in the Cancer Prevention Division is primarily focused on the anticarcinogenic properties of a wide variety of natural and synthetic substances. Elucidation of the mechanisms of action of cancer preventive substances is also a main objective. The results obtained are anticipated to facilitate the development of preventive measures against human cancers.
Suppression of Colon Carcinogenesis by Docosahexaenoic Acid
Diets rich in fish containing w3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are reported to be related to a low risk of colon cancer in man. In order to confirm these epidemiological findings experimentally, the effects of DHA on colon carcinogenesis were investigated in rats. Male F344 rats were treated with subcutaneous injections of 15 mg/kg of azoxymethane (AOM) once a week, for 2 weeks. Rats were divided into control and DHA-treated groups. Rats in the DHA-treated group were given 1 ml of DHA each intragastrically 5 times a week for 36 weeks, starting the day before the first AOM treatment and continuing throughout the experiment. The incidence of animals bearing colon tumors was 92% in the DHA-treated group and 96% in the control group. However, the number of colon tumors per rat was significantly lower in the DHA-treated group (2.45}1.63) than in the control group (3.78}2.19). The chemopreventive effect of DHA was also investigated in terms of the formation of aberrant crypt foci (ACF), which are putative preneoplastic lesions of the colon, induced by the food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Male F344 rats were given PhIP intragastrically (75 mg/kg) 5 times a week for 2 weeks. DHA was administered to the rats as described above. The number of ACF per colon decreased significantly with administration of DHA for 4 and 12 weeks, being 47% and 38% of the respective control values. These results support the chemopreventive efficacy of DHA against colon carcinogenesis. Decreases in prostaglandin E2 production and DNA adduct formation were suggested to be involved in the chemopreventive effect of DHA.
Suppression of Nitric Oxide Production in Lipopolysaccharide-stimulated Macrophage Cells by w3
Polyunsaturated Fatty Acids
Although nitric oxide (NO) is an important biological mediator, its excessive production in inflammation is thought to be a causative factor in cellular injury and cancer development. The effects of several fatty acids on NO production in the murine macrophage cell line RAW264 were therefore examined after stimulation with lipopolysaccharide (LPS). Dose dependent suppression of NO production was demonstrated with the w3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA), eicosa-pentaenoic acid (EPA) and a-linolenic acid. In contrast, no inhibition was observed with an w6 PUFA (linoleic acid), an w9 PUFA (oleic acid) and a saturated fatty acid (stearic acid). Western and Northern blot analyses suggested that suppression of the induction of inducible NO synthase (iNOS) gene expression is responsible for the inhibition of NO production by w3 PUFAs. Thus, it was suggested that the inhibitory effect of w3 PUFAs on NO production in activated macrophages may contribute to their cancer chemopreventive effect.
Suppression of Rat Colon Carcinogenesis by Nimesulide,
a Selective Inhibitor of Cyclooxygenase 2
Non-steroidal anti-inflammatory drugs, such as piroxicam and sulindac, are known to exhibit chemopreventive effects on colon carcinogenesis. However, they also cause gastrointestinal side-effects. Nimesulide is a selective inhibitor of cyclooxygenase 2 (COX-2) which has been shown to be a more potent anti-inflammatory agent than piroxicam, but less ulcerogenic. Therefore, nimesulide is possibly more useful for chemoprevention. To assess this possibility, the inhibitory effects of nimesulide on AOM-induced ACF formation were investigated and compared with those of piroxicam and sulindac. Nimesulide at doses of 50, 100 and 200 ppm reduced the numbers of AOM-induced ACF to 75%, 71% and 65%, respectively, of the control value. The number of AOM-induced ACF per colon in the group given 200 ppm nimesulide was nearly the same as in those given 200 ppm piroxicam, and lower than that in the group given 200 ppm sulindac. It was thus suggested that nimesulide, a selective COX-2 inhibitor, warrants attention as a potential chemopreventive agent in colon carcinogenesis.
The anticarcinogenic effects of a wide variety of natural materials and their related compounds have also been assessed. Reports related to these investigations can be found in the attached list of publications.(123,124)
List of papers from this division
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