Etiology Of Colon Cancer Research Articles

Bile acids (BA)arrest colonic cell proliferation in a cell cycle-dependent fashion

Epidemiological studies link factors that influence concentration of soluble fecal BA to etiology of colon cancer. BA promote tumor growth in vivo and increase cell transformation in vitro. HYPOTHESIS: BA alter normal cycle of colonic cell proliferation. AIM: to study cell cycle-dependent effects of BA on cell proliferation in the human colon cancer cell line, HT29. Cells were seeded at 4 x 104/cm2 . 24h later, medium was replaced with serum-free medium to render cells quiescent. GO/GI arrest was confirmed by flow cytometry. After 24h, 0.5% FBS was added to stimulate proliferation (TO), and either PBS (control), 50pM chenodeoxycholate (CDC), deoxycholate (DC), or ursodeoxycholate (UDC) were added to 112 of wells. 24h later, (T24), cells were washed to remove agents, and fresh 0.5% FBS-containing medium was added, while the same agents were freshly added to the other 112 of wells. 48h after TO (T48), DNA content was measured using a fluorescent oligonucleotide binding probe. In parallel, cells were counted with a hemocytometer, following trypan blue staining. There was no difference in number between cells exposed to either PBS or UDC, while there was a significant decrease in cell number after exposure to both CDC and DC for TO-T24. Decrease in cell number observed with DC incubation was linearly correlated with DNA content. This is consistent with either DC-induced growth arrest, or increased cell death. The latter is unlikely, since there was no change in number of either trypan-permeable (dead) cells or unattached cells after DC or CDC exposure. In contrast, the 50% decrease in cell number after TO-T24 CDC incubation was accompanied by a DNA content per cell that was 2 fold greater compared to that of control, DC or UOc. We conclude that CDC induces G2 arrest, in that DNA has been replicated without cell division. This is consistent with the observation that population doubling (PD) time of GO/GI synchronized HT29 cells is around 30-38h, as determined initially, and subsequently, 18 to 24h following addition of 0.5% FBS. Therefore by T48, I PD would have occurred. In sharp contrast to these findings, cells exposed to BA from T24-T48, showed no decrease in either cell number or DNA content. Thus the ability of DC and CDC to block cell proliferation was only observed with GO/GI synchronized cells. Results of this study show that certain BA alter normal cell cycle progression in a cell cycle-dependent fashion. Dysregulation of cell cycle control may be one mechanism by which BA induce their co-carcinogenic effects.

The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer

Animal models provide a unique opportunity to study the biology of the disease process, and to test hypotheses linking environmental factors in the etiology and prevention of colon cancer. The concept of cancer prevention is to retard, regress or eliminate precancerous lesions. To actuate this concept, it is important to identify and enumerate preneoplastic lesions of various growth dimensions. The study of the precancerous stages in the colon is possible by the identification of aberrant crypt foci (ACF) in rodent colons treated with a carcinogen. The growth, morphological and molecular features of ACF support the contention that ACF are putative preneoplastic lesions. The ACF system is used extensively to identify modulators of colon carcinogenesis. Among the various endpoints being used in cancer research, ACF are the only endpoints which provides a quantitative approach to assess the disease process and the underlying cellular and molecular events as affected by cancer preventive or promoting agents. Many dietary components have been classified as tumor promoters or inhibitors based on their ability to change the tumor outcome. Whether they affect the growth of very early or advanced preneoplastic lesions is not known and can be explored by using ACF system. This information will provide a better understanding of cancer pathogenesis and will lead to the development of different cancer preventive strategies for high-risk individuals and the general population.

Phospholipid fatty acid composition and protein kinase C activity in the large intestine of rats fed on butter and coconut-oil diets.

Protein kinase C (PKC) has been proposed to play an important role in the aetiology of colon cancer. Therefore, we investigated whether the amount and type of saturated fat could affect colonic PKC activity by modifying either mucosal phospholipid fatty acid composition or faecal diacylglycerol production. Male Wistar rats (n 13 per group) were fed on diets containing butter or coconut oil at energy levels of 10% and 43% for 4 weeks. The control group received a low-fat diet providing 10% of energy from sunflowerseed oil. PKC activity was higher in the distal than the proximal colon but the quantity or type of fat did not alter PKC activity in either region of the colon. Saturated fats caused moderate changes in the fatty acid composition of caecal phospholipids, which were more obvious in the phosphatidylethanolamine than in the phosphatidylcholine fraction. A significant correlation was found between fatty acid composition of phosphatidylcholine and membrane PKC activity. In particular, there was a positive correlation between the proportion of saturated 14:0 and 18:0 and increased PKC activity while unsaturated 18:2n-6, 20:4n-6 and 16:1n-7 were inversely correlated with PKC activity. No relationship was found between phosphatidylethanolamine fatty acids and PKC activity. Concentration of faecal diacylglycerol was not affected by the diet. Overall the data suggest that diets high in saturated fat may not alter colonic PKC activity to a significant extent.

Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps.

Cooked-food mutagens formed when frying meat have been suggested to contribute to the etiology of colon, breast and prostate cancer. The most prevalent of these mutagens is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which after absorption is bioactivated by both phase I and phase II enzymes. Although available data suggest absorption of PhIP in humans, the extent and mechanism of absorption are unknown. In the present study we examined the transport of [(3)H]PhIP through the human Caco-2 intestinal epithelial cell monolayer, a well-accepted model of human intestinal absorption. The influx, or absorption, was extensive and linear for 2 h and up to a PhIP concentration of 5 microM. Still, the basolateral to apical efflux [apparent permeability coefficient (P(app)) 54.2 +/- 0.7x10(-6) cm/s, mean +/- SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (P(app) 15.1 +/- 0.6x10(-6) cm/s, n = 21, P < 0.0001). Equilibrium exchange experiments demonstrated the efflux to be a true active process. Preincubations with verapamil, an inhibitor of P-glycoprotein-mediated transport, or MK-571, an inhibitor of multidrug resistance-associated protein-mediated transport, stimulated influx and reduced efflux of PhIP, suggesting that PhIP is a substrate for both of these transporters. These findings should be considered when determining exposure to the cooked food mutagens.

Lifestyle and colon cancer: an assessment of factors associated with risk.

Studies of the etiology of colon cancer indicate that it is strongly associated with diet and lifestyle factors. The authors use data from a population-based study conducted in northern California, Utah, and Minnesota in 1991-1995 to determine lifestyle patterns and their association with colon cancer. Data obtained from 1,993 cases and 2,410 controls were grouped by using factor analyses to describe various aspects of lifestyle patterns. The first five lifestyle patterns for both men and women loaded heavily on dietary variables and were labeled: "Western," "moderation," "calcium/low-fat dairy;" "meat and mutagens," and "nibblers, smoking, and coffee." Other important lifestyle patterns that emerged were labeled "body size," "medication and supplementation," "alcohol," and "physical activity." Among both men and women, the lifestyle characterized by high levels of physical activity was the most marked lifestyle associated with colon cancer (odds ratios = 0.42, 95% confidence interval: 0.32, 0.55 and odds ratio = 0.52, 95% confidence interval: 0.39, 0.69, for men and women, respectively) followed by medication and supplementation (odds ratio = 1.68, 95% confidence interval: 1.29, 2.18 and odds ratio = 1.63, 95% CI 1.23, 2.16, respectively). Other lifestyles that were associated with colon cancer were the Western lifestyle, the lifestyle characterized by large body size, and the one characterized by calcium and low-fat dairy. Different lifestyle patterns appear to have age- and tumor site-specific associations.

Red meat consumption in Australia: intakes, contributions to nutrient intake and associated dietary patterns.

In the past few decades, increasing concern about the role of diet in the aetiology of diseases such as heart disease and certain cancers, including colon cancer and the hormone-related cancers, has led to a number of studies assessing the role of various food components. Many of these studies, particularly those in the 1970s and 1980s looked at individual foods or nutrients without assessing their role in relation to other dietary components. Thus the role of red meat was often examined in isolation from energy, fat or fibre intake or from consumption of other food groups such as vegetables or fruit. Epidemiological studies of the dietary aetiology of colon cancer have been undertaken in a number of communities with varying meat and dietary intake profiles and with varying results. To provide background information for an assessment of the potential role of red meat consumption in the aetiology of colon cancer in the Australian context, an analysis of current consumption patterns of red meat in the population was undertaken. The results show that red meat consumption, which had been falling since the 1970s, continued to decline in Australia at a time when colon cancer rates were rising. Red meat intake in 1995/6 averaged 88 g a day for men and 45 g a day for women and was contributing less than one-fifth of the dietary fat and saturated fat in the Australian diet. Those with the highest intakes of red meat on the day of the survey had intakes of vegetables and fruits closer to those of non-red meat eaters, with the low-to-moderate red meat consumers having the lower intakes of fruits and vegetables.

Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4, 5-b]pyridine by human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A family isoforms involved.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a heterocyclic aromatic amine found in cooked meats and dietary exposure to PhIP has been implicated in the etiology of colon cancer in humans. PhIP, along with other heterocyclic aromatic amines, requires metabolic activation to exhibit genotoxic effects. PhIP is initially oxidized by the activity of cytochrome P4501A2 to produce 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), a reaction occurring primarily in the liver. Whereas subsequent biotransformation of N-OH-PhIP via acetylation or sulfation can produce reactive electrophiles that readily bind to DNA, N-glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), functions as a detoxification mechanism. Although hepatic glucuronidation of N-OH-PhIP has been well characterized, the extrahepatic metabolism of this compound is poorly understood. Studies in our laboratory now indicate that the intestinal tract, and particularly the colon, is a significant site of glucuronidation of N-OH-PhIP. When assays were performed with microsomes prepared from the mucosa of the intestinal tract, it was determined that glucuronidation of N-OH-PhIP occurs throughout the intestinal tract, with activity approximately three times higher in the colon as that found in the upper intestine. Glucuronidation rates from colon microsomes showed considerable interindividual variability and incubation with N-OH-PhIP yielded two glucuronides. HPLC analysis showed that the predominant product formed is the N-OH-PhIP-N2-glucuronide, while the N3-glucuronide accounts for <10% of the total glucuronidation product. These rates approach the rates found in human liver microsomes, demonstrating the significance of extrahepatic metabolism of this food-borne carcinogen. Subsequent assays with human recombinant UGTs demonstrated that at least four human UGT isoforms, all from the UGT1A subfamily, are capable of catalyzing the biotransformation of N-OH-PhIP. Members of the UGT2B family available for this study did not conjugate N-OH-PhIP, although immunoinhibition studies in human liver microsomes strongly suggest the involvement of a UGT2B isoform(s) in this organ.

Effect of dietary deoxycholic acid and cholesterol on fecal steroid concentration and its impact on the colonic crypt cell proliferation in azoxymethane-treated rats

To elucidate the role of fecal steroids in the malignant tumor formation of colonic epithelial cells, we examined the effects of dietary deoxycholic acid (DCA) and cholesterol (CHL) on fecal steroid concentrations and their impact on colonic crypt cell proliferation. Twenty 5-week-old male Fischer 344 rats were provided with either a control semisynthetic diet or the same diet supplemented with 0.15% DCA and 1% CHL (steroid diet) over a 5-week period. The effects of these two diets were compared among rats that were either injected with azoxymethane (AOM), a known gastrointestinal carcinogen, or saline. In a 2×2 factorial design, rats fed each of these diets were given two weekly subcutaneous injections of either AOM (15 mg/kg b.w.) or saline at 6 and 7 weeks of age. At 9 weeks of age, fecal samples were obtained for analysis of bile acids, CHL and its bacterial metabolites of intestinal microflora. At 10 weeks of age, animals were sacrificed and colonic proliferation was assessed as vincristine-accumulated mitotic figures per crypt. Rats fed the steroid diet had significantly elevated fecal bile acid (5×, P<0.001) and neutral steroid (10×, P<0.01) levels when compared to those fed the control diet. AOM treatment did not appear to influence these levels. However, rats injected with AOM had a significant increase ( P<0.001) in their rate of colonic cell proliferation as compared to saline-injected control animals on both diets. Furthermore, rats fed the steroid diet had a significantly higher ( P<0.001) cell proliferation rate than animals fed the control diet. The effects of AOM treatment and the steroid diet on cell proliferation were additive. Our results demonstrate that high concentrations of neutral and acid steroids in the colonic lumen can enhance carcinogen-induced elevated cell proliferation and thus may play a key role in the etiology of colon cancer.

The role of fat, fatty acids, and total energy intake in the etiology of human colon cancer

A high correlation between national per capita disappearance of fat and national rates of colon cancer led to the hypothesis that consumption of fat, especially from animal sources, increases risk for colon cancer. Over the past two decades, this hypothesis has been tested in numerous case-control and cohort studies. In general, neither case-control nor cohort studies find that the total fat composition of the diet increases risk of colon cancer. Case-control studies frequently find that total energy consumption is related to a higher risk of colon cancer, but this result is difficult to interpret because physical activity appears to be protective whereas obesity increases risk. In contrast with the results for total fat, epidemiologic data regarding the role of specific fatty acids are sparse. Nonetheless, useful information regarding major fatty acids may be inferred from the numerous studies that have examined major source of various fats in relation to colon cancer. Intake of red meat or beef has been related to colon cancer risk in most case-control and cohort studies, whereas dietary fat from sources other than red meat, including dairy, poultry, and vegetable oils, does not increase risk of colon cancer. The apparent influence of red meat does not appear to be mediated through its total lipid content, suggesting that other factors such as heterocyclic amines formed during cooking may be critical. Mechanisms whereby fat or red meat may influence colon carcinogenesis are discussed, although none appear compelling.

BIM1 encodes a microtubule-binding protein in yeast.

A previously uncharacterized yeast gene (YER016w) that we have named BIM1 (binding to microtubules) was obtained from a two-hybrid screen of a yeast cDNA library using as bait the entire coding sequence of TUB1 (encoding alpha-tubulin). Deletion of BIM1 results in a strong bilateral karyogamy defect, hypersensitivity to benomyl, and aberrant spindle behavior, all phenotypes associated with mutations affecting microtubules in yeast, and inviability at extreme temperatures (i.e., >/=37 degrees C or </=14 degrees C). Overexpression of BIM1 in wild-type cells is lethal. A fusion of Bim1p with green fluorescent protein that complements the bim1Delta phenotypes allows visualization in vivo of both intranuclear spindles and extranuclear microtubules in otherwise wild-type cells. A bim1 deletion displays synthetic lethality with deletion alleles of bik1, num1, and bub3 as well as a limited subset of tub1 conditional-lethal alleles. A systematic study of 51 tub1 alleles suggests a correlation between specific failure to interact with Bim1p in the two-hybrid assay and synthetic lethality with the bim1Delta allele. The sequence of BIM1 shows substantial similarity to sequences from organisms across the evolutionary spectrum. One of the human homologues, EB1, has been reported previously as binding APC, itself a microtubule-binding protein and the product of a gene implicated in the etiology of human colon cancer.

Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1.

Cytochrome P4501B1 (CYP1B1) is the most recently identified member of the dioxin-inducible CYP1 family. CYP1B1 is constitutively expressed in most human tissues, including colon and breast, and can activate numerous chemically diverse carcinogens. We evaluated the metabolism of the dietary heterocyclic amine carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by microsomes from yeast expressing the human CYP1B1 protein. PhIP metabolites were analysed by HPLC with fluorescence and absorbance detection. We found that human CYP1B1 metabolizes PhIP to three products: N2-OH-PhIP, a mutagenic activation product; 4'-OH-PhIP, a detoxification product; and 2-OH-PhIP, the mutagenic potential of which is unknown. Metabolite identity was confirmed by co-elution with authentic standards and synchronous fluorescence spectroscopy. The identity of the 2-OH-PhIP standard was additionally confirmed by mass spectrometry. Kinetic studies of the formation of N2-OH-PhIP, 4'-OH-PhIP and 2-OH-PhIP by CYP1B1 indicated apparent Km values of 5.7 +/- 1.3, 2.2 +/- 0.5 and 1.3 +/- 0.2 microM, respectively. Apparent turnover rates were 0.40 +/- 0.03, 0.93 +/- 0.02 and 0.04 +/- 0.00 nmol product/min nmol P450, respectively. At saturating levels of substrate, CYP1B1-mediated formation of the non-mutagenic metabolite 4'-OH-PhIP was favored two-fold over that of the mutagenic metabolite, N2-OH-PhIP and >10-fold over that of 2-OH-PhIP. The formation of N2-OH-PhIP, a potent mutagen implicated in the etiology of human colon and breast cancer, indicates that CYP1B1 may play an important role in PhIP-mediated carcinogenesis.

Tocopherols and the etiology of colon cancer.

Colorectal cancer is the second most common cause of cancer deaths in the United States for both sexes. Considerable evidence suggests that the risk of this cancer is increased by the mutagenic actions of free radicals, which are produced during oxidation reactions. Dietary factors, the intestinal flora (bacteria), and endogenously produced metabolites contribute to the production of free radicals in the colon. Dietary antioxidants, such as vitamin E, should reduce the levels of these harmful oxidation products. In the absence of vitamin E, polyunsaturated fats can be oxidized in the colon to produce mutagens, such as lipid hydroperoxides and malondialdehyde. Furthermore, fecal bacteria can generate a high flux of reactive oxygen species (e.g., the superoxide radical [O2*-]) at the surface of the intestinal lumen, and inflammatory cells in close proximity to the colon can produce reactive nitrogen species (e.g., nitrogen dioxide [NO2]). Increasing evidence suggests that the different chemical (e.g., alpha- and gamma-tocopherol) and stereochemical (e.g., RRR- and all-racemic-alpha-tocopherol) forms of vitamin E have distinct biologic potencies, pharmacokinetics, and different abilities to prevent neoplastic transformation. This review considers and evaluates recent studies relating vitamin E and oxidative stress to colon cancer, emphasizing the distinct roles of alpha- and gamma-tocopherols. In addition, recent findings on the antioxidant/pro-oxidant status of the digesta (ingested food) are discussed with respect to the use of antioxidants in chemo-prevention trials for colon cancer.

Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) in the rat

The mutagenic heterocyclic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP), is a pyrolysis product in cooked foods that has been shown to be a rat colon carcinogen and has been implicated in the etiology of human colon cancer. In order to identify chemoprotection strategies that could be carried out in humans, a pilot study was conducted in which PhIP–DNA-adduct levels were quantified in the colons of male F344 rats that had been subjected to 16 different putative chemoprotection regimens, followed by a gavage of PhIP (50 mg/kg) and sacrifice 24 h later. The 16 treatments (Oltipraz, benzylisothiocyanate, diallyl sulfide, garlic powder, ethoxyquin, butylated hydroxyanisole, glutathione, indole-3-carbinol, α-angelicalactone, kahweol/cafestol palmitates, quercetin, green tea, black tea, tannic acid, amylase-resistant starch, and physical exercise) comprised sulfur-containing compounds, antioxidants, flavonoids, diterpenes, polyphenols, high dietary fiber, etc. The strongest inhibition of PhIP–DNA adduct formation in the colon was observed upon pretreatment with black tea, benzylisothiocyanate, and a mixture (1:1) of kahweol:cafestol palmitates, which resulted in 67, 66, and 54% decreases in colon PhIP–DNA adduct levels, as compared with controls. Preliminary studies on their mechanism of action indicated that only kahweol:cafestol caused a substantial induction of glutathione S-transferase isozymes (GSTs) that are thought to be important in the detoxification of PhIP. Notably, this induction occurred in the liver rather than in the colon.

Induction of DNA damage by risk factors of colon cancer in human colon cells derived from biopsies

In order to increase the understanding of the factors responsible for causing human colon cancer, a technique was developed to detect genotoxic effects of chemicals in human colon cells. Risk factors suspected to be associated with the aetiology of human colon cancer were subsequently investigated: the method is based on the measurement of DNA damage in primary cells freshly isolated from human colon biopsies with the single cell microgel ectrophoresis technique (`Comet Assay'). 2-Amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP), 2-amino-3-methyl-3 H-imidazo[4,5 f]quinoline (IQ), N-methyl- N-nitro- N-nitrosoguanidine (MNNG), dinitrosocaffeidine (DNC) lithocholic acid (LCA), hydrogen peroxide (H 2O 2) and benzo[ a]pyrene (B[a]P) were investigated for their genotoxic and cytotoxic effects following 30 min incubation with colon cells of human, and for comparative purposes also of the rat colon. The nitrosamides (MNNG, DNC) were very genotoxic in human colon cells. MNNG was more genotoxic in human than in rat colon cells. In contrast, the rat colon carcinogens PhIP and IQ were not genotoxic in human colon cells. PhIP did induce DNA damage in rat colon cells, which correlates to its capacity of inducing tumors in this animal tissue. LCA was toxic (rat>human) and concomitantly caused DNA damage in higher concentrations. The widespread contaminant B[a]P was not genotoxic in colon cells of either species using this system. H 2O 2 was found to be a potent genotoxic agent to both rat and human colon cells (human>rat). In summary, those compounds chosen as representatives of endogenously formed risk factors (MNNG, H 2O 2, LCA) have a higher toxic and/or genotoxic potency in human colon tissue than in rat colon. They are also more effective in this system than the contaminants tested so far (B[a]P, PhIP, IQ). The newly developed technique is rapid and yields relevant results. It is a novel and useful approach to assess different chemical compounds for genotoxic activities in tumour target tissues of the human.

Diet and Carcinogen Alter the Fecal Microbial Populations of Rats1,2

An analysis of viable bacterial populations enumerated on carbohydrate selective media was used to simulate the colonic environment in vitro and determine if differential media could detect significant microbial shifts due to dietary fiber source, dietary fat source, and carcinogen. Male Sprague-Dawley rats were provided with either pectin or cellulose as a fiber source, either corn or fish oil as a source of fatty acids, and injected with either azoxymethane (AOM), a gastrointestinal carcinogen, or saline in a 2 x 2 x 2 factorial design. At 6 and 10 mo of age, fresh feces were collected, homogenized in anaerobic buffer and anaerobically plated onto differential media. Diets containing pectin supported more anaerobes at 6 mo of age (P < 0.01) than diets containing cellulose. Rats injected with AOM and consuming either pectin or corn oil supported more anaerobes at 10 mo of age (P < 0.05) than rats injected with saline and consuming the same diets. Rats consuming cellulose and receiving AOM but not expressing tumors possessed larger anaerobic populations at 10 mo of age (P < 0.05) than rats consuming cellulose, injected with AOM and expressing tumors. These effects show that gastrointestinal bacterial populations, as measured by carbohydrate specific media, respond to dietary changes such as dietary fiber source, and thus may play a key role in the etiology of colon cancer.

Structural requirements for enhancement of EGF-dependent DNA synthesis by oxygenated metabolites of linoleic acid.

Epidemiological and animal model studies suggest a link between high dietary fat intake and the etiology of colon and breast cancer (1,2). In particular, linoleic acid, as the major polyunsaturated fatty acid consumed by humans, enhances tumorigenesis in several model systems (3–5). Our previous work suggests a role for specific oxygenated metabolites of linoleic acid in modulating cell proliferation and/or transformation (6,7). In Syrian hamster embryo (SHE) fibroblasts, we observed potentiation of epidermal growth factor (EGF)-dependent mitogenesis by 13-hydroxyoctadecadienoic acid (HODE), the primary linoleate metabolite formed in these cells. The mechanism of action by which linoleate derivatives enhance EGF-regulated [3H]thymidine incorporation has not been established. As an initial approach to investigate this area, we examined the structural characteristics of bioactive lipid compounds related to stimulation of DNA synthesis in SHE cells.

Interplay between heterocyclic amines in cooked meat and metabolic phenotype in the etiology of colon cancer.

Although the etiology of colon cancer remains uncertain, an increasing body of epidemiologic evidence indicates that red meat consumption is an important risk factor. The cooking of red meat produces a class of potent experimental carcinogens, the heterocyclic aromatic amines (HAA). These induce cancers in several different sites, including the colon, in rats and mice. Other epidemiologic studies indicate that an individual's genetically determined metabolic phenotype (polymorphisms for N-acetyltransferase and N-hydroxylase) modulates the risk of colon cancer. Both N-acetyltransferase and N-hydroxylase are involved in the metabolism of HAA. An increased risk of colon cancer has been observed in rapid acetylators in four of five studies; further, in two of these the association was found only in meat eaters. The latter observation supports the hypothesis that HAA are involved in colon carcinogenesis. Considerable progress has been made in the study of the molecular pathogenesis of colon cancer, which typically entails the cumulation of several genetic events (mutations and deletions) in oncogenes and tumor suppressor genes. It would now be a crucial contribution to elucidating the causation of colon cancer to show that such mutations are induced in human colonic mucosa by food-borne heterocyclic aromatic amines.

Nutritional factors and colon cancer.

During the last 2 decades, substantial progress has been made in understanding the relationship between dietary constituents and the development of colon cancer in man. Unlike studies of cancer among smokers and nonsmokers, nutritional epidemiologic studies are confronted with the inherent difficulty of assessing reasonably precise exposures. The lack of consistency between international correlation studies and case-control studies does not necessarily negate a dietary etiology of colon cancer because these inconsistencies may have arisen, at least in part, from methodological limitations. Some of these deficiencies in epidemiological studies of diet and cancer have been corrected; recent case-control studies demonstrated that high dietary fat is a risk factor for colon cancer development and that an overall increase in intake of foods high in fiber might decrease the risk for colon cancer. The results of epidemiologic studies may be assumed to present conservative estimates of the true risk for cancer associated with diet. The populations with high incidences of colon cancer are characterized by high consumption of dietary fat, which may be a risk factor in the absence of factors that are protective, such as whole-grain cereals and of other high fiber. Laboratory-animal model studies have shown that certain dietary lipids and fibers influence tumorigenesis in the colon. The data of metabolic epidemiological and laboratory-animal model studies are sufficiently convincing with respect to the enhancement of colon cancer by type of fat and protection by certain dietary fibers.

Chemoprevention of colon cancer by dietary fatty acids.

During the last two decades, substantial progress has been made in the understanding of the relationship between the dietary constituents and development of colon cancer in man. Unlike studies of cancer among smokers and nonsmokers, nutritional epidemiologic studies are confronted with the inherent difficulty of assessing reasonably precise exposures. The lack of consistency between international correlation studies and case-control studies does not necessarily negate a dietary etiology of colon cancer because these inconsistencies may have arisen, at least in part, from methodological limitations. Some of these deficiencies in epidemiological studies of diet and cancer have been corrected; recent case-control studies demonstrated that high dietary fat is a risk factor for colon cancer development and that an overall increase in intake of foods high in fiber might decrease the risk for colon cancer. The results of epidemiologic studies may be assumed to present conservative estimates of the true risk for cancer associated with diet. The populations with high incidence of colon cancer are characterized by high consumption of dietary fat, which may be a risk factor in the absence of factors that are protective, such as whole-grain cereals and of other high-fiber. Laboratory animal model studies have shown that certain dietary lipids and fibers influence tumorigenesis in the colon. The data of metabolic epidemiological and laboratory animal model studies are sufficiently convincing with respect to enhancement of colon cancer by type of fat and protection by certain dietary fibers.

Differential long-term dietary behavior effects of colon cancer prevention programs

Increasing recognition of the importance of diet in the etiology of colon cancer has highlighted the need for methods to determine dietary intake of high risk nutrients. Colon cancer prevention programs (CCPPs) promote consumption of low fat, high fiber diets rich in fruits and vegetables. The purpose of this study was to examine one-year follow-up dietary habits and to determine differences between perceived and actual levels of fat intake in older adults who had participated in CCPPs involving either beta carotene or calcium-wheat bran fiber supplementation. Frequency of foods actually eaten and perceived level (high, medium or low) of fat intake were assessed using the Centers for Disease Control Behavior Risk Factor Survey (BRFS). A telephone survey was administered to 103 previous CCPP participants (average age 64). Differences in estimated grams of fat eaten were compared to perceived level of fat intake using one-way ANOVA. The BRFS-derived weekly fat intake estimates ranged from 38 to 447 grams. Compared to subjects reporting high or medium fat intake, those reporting low fat intake had significantly (p<.05) lower total weekly fat consumption. Furthermore, subjects who perceived their fat intakes as low also actually reported consuming significantly (p<.05) more fruits and vegetables and fewer servings of high fat meats. Expected differences by study were not found with subjects from the beta carotene trial not consuming significantly (p<.05) more servings of carrots as compared with the calcium-wheat bran fiber group. Likewise, calcium-wheat bran fiber participants did not consume higher amounts of calcium-rich foods. Although all subjects tended to consume low fat diets, many did not continue to eat foods rich in beta carotene or calcium and wheat bran fiber. These results suggest general, not specific, dietary behavior carry-over effects one year after participation in a CCPP