1-(1-glycero)dodeca-1-3-5-7-9-pentaene and Colonic-Neoplasms

Topics: Cell Division; Colon; Colonic Neoplasms; Diet; Feces; Humans; Lipids; Polyenes

The response of Escherichia coli to genotoxic agents involves the triggering of a complex system of genes known as the SOS response. In E. coli PQ37, a test organism used for the assessment of genotoxicity, lacZ, the beta-galactosidase gene is placed under the control of sfiA, one of the SOS genes through an operon fusion. The induction of beta-galactosidase activity, when the organism is exposed to genotoxic agents, is an indirect measure of the genotoxic activity of the test compound. Incubation of E. coli PQ37 with either 4-nitroquinoline oxide (4-NQO) or one of the fecal mutagens, fecapentaene-12 or -14 (F-12 or F-14) in the presence of sodium taurocholate or sodium deoxycholate resulted in a significant enhancement of induction of beta-galactosidase activity. The molecular mechanisms of 4-NQO-induced mutagenesis in E. coli are similar to those of the effects of UV light in which both replication-dependent and repair-dependent pathways of mutagenesis exist. Since E. coli PQ37 is excision-repair-deficient, alternate pathways are involved in this system. Bile salts by themselves do not trigger the SOS response, and hence their role in enhancing the SOS-inducing potency of mutagens may involve the potentiation of the cleavage-inactivation of lexA (repressor of SOS) by the protein product of the SOS-controlled gene, recA. The potentiating effect of bile salts on the fecal mutagens, F-12 and F-14, has implications in their suspected role in colon carcinogenesis associated with high-fat, low-fiber diets.

Topics: 4-Nitroquinoline-1-oxide; Alkaline Phosphatase; Bile Acids and Salts; Colonic Neoplasms; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Synergism; Escherichia coli; Lithocholic Acid; Mutagens; Polyenes; SOS Response, Genetics; Taurocholic Acid; Ultraviolet Rays

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.

Topics: Antineoplastic Agents; Caffeic Acids; Colonic Neoplasms; Curcumin; Cyclooxygenase 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; I-kappa B Kinase; I-kappa B Proteins; Isoenzymes; Membrane Proteins; NF-kappa B; NF-kappaB-Inducing Kinase; Phenylethyl Alcohol; Polyenes; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Signal Transduction; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Fecapentaenes are a group of fecal mutagens produced by anaerobic microflora of the colon. The potential of fecapentaene-12 (FP-12) to promote tumor development was tested in a rat colon carcinogenesis model using N-methyl-N-nitrosourea (MNU) as the initiating agent. Two groups of female F-344 rats were initiated by intrarectal instillations of MNU (2 mg in 0.5 ml H2O, 3 times a week, for 3 weeks; MNU and MNU + FP-12 groups). Two additional groups (FP-12 and Control) were given H2O without carcinogen. In the post-initiation phase, rats of the MNU + FP-12 and FP-12 groups were intrarectally administered 400 ng of FP-12 in 0.5 ml T-E buffer, twice a week, for 24 weeks, whereas the MNU and Control groups received the vehicle only. Tumors were found only in the MNU and MNU + FP-12 groups, their number being higher in the latter. The number of carcinoma bearing rats as well as the average number of carcinomas per rat were significantly higher (P < 0.05) in the MNU + FP-12 group as compared to the MNU-alone values. Aberrant crypt foci (ACF) were found in all carcinogen-treated rats, including those that did not contain tumors, whereas none were observed in the FP-12 and Control groups. The average number of ACF/cm2 was also significantly higher in the MNU+FP-12 group, as was the case for the average number of ACF containing > 10 aberrant crypts per focus. These findings suggest that FP-12 can express promoting activity in chemical induced colon carcinogenesis.

Topics: Animals; Carcinogens; Cocarcinogenesis; Colonic Neoplasms; Disease Models, Animal; Female; Intestinal Mucosa; Methylnitrosourea; Polyenes; Rats; Rats, Inbred F344

Fecapentaenes, a class of direct-acting bacterial mutagens, have been isolated from the feces and intestinal tract of humans on a Western meat-containing diet. Two bioassays to test pure fecapentaene-12 (FP-12) for carcinogenicity were performed. FP-12 in dimethylsulfoxide (DMSO) solution was injected i.p. into newborn ICR/MA mice on days 1, 3, 7, 10, 14 and 21. The mice killed after 21 months had neoplasms in liver, lung, glandular stomach and subcutaneous fibrosarcoma. Intrarectal (i.r.) infusion of FP-12 in an aqueous vehicle into male F344 rats for 71 weeks, and killing the rats after 21 weeks more, displayed no evidence of neoplasia associated with FP-12 exposure. The positive control, N-nitrosomethylurea (NMU), given i.r. as 4 2-mg doses in 2 weeks, as expected, yielded multiple colonic neoplasms in less than 11 months. Fecapentaene may exert its effect in bacteria and in newborn mice through the generation of hydroxy radicals. However, adult rodent and human colon may have adequate biochemical defense mechanisms against low level, even continuous exposures to chemicals like FP-12, and thus be at low risk of neoplasia, as was found.

Topics: Adenoma; Animals; Animals, Newborn; Carcinogenicity Tests; Carcinogens; Colonic Neoplasms; Female; Fibrosarcoma; Leukemia, Experimental; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Polyenes; Rats; Rats, Inbred F344; Sex Factors; Skin Neoplasms; Stomach Neoplasms

Fecapentaenes are mutagens found in human feces and may play a role in the pathogenesis of colon carcinoma. However, the genotoxic effects of fecapentaenes have not been previously studied in mammalian cells. We now report that fecapentaene-12 (fec-12), a prototype for these compounds, causes DNA single strand breaks, sister chromatid exchanges and mutations in cultured human fibroblasts. These results indicate that fec-12 is a potent genotoxic agent in human cells.

Topics: Cells, Cultured; Colonic Neoplasms; DNA; Dose-Response Relationship, Drug; Humans; Mutagens; Mutation; Polyenes

Topics: Bile Acids and Salts; Carcinogens; Cholesterol; Colonic Neoplasms; Diet; Dietary Fats; Feces; Humans; Ketosteroids; Mutagenicity Tests; Mutagens; Polyenes; Structure-Activity Relationship

Topics: Adult; Bacteroides; Carcinogens; Colonic Neoplasms; Feces; Female; Humans; Male; Middle Aged; Mutagens; Polyenes