N-nitrosation of proline in smokers and nonsmokers.

Endogenous nitrosation of proline was investigated in smokers and nonsmokers. Volunteers consumed a volume of beet juice equivalent to 325 mg nitrate, and 1 hour later they consumed 500 mg proline. In separate experiments volunteers ingested proline alone. Twenty-four-hour urine samples were collected and analyzed for N-nitrosoproline. When proline alone was ingested, there was no significant difference in urinary nitrosoproline excretion between smokers and nonsmokers. When beet juice and proline were consumed, however, smokers produced approximately 2.5 times as much N-nitrosoproline as nonsmokers. Salivary thiocyanate levels were approximately 3.2 times higher in smokers compared to those in nonsmokers. Salivary nitrite levels of smokers and nonsmokers, either before or after beet juice consumption, were not different. Salivary nitrate concentrations, however, were higher in nonsmokers than in smokers after beet juice consumption but not before. Our results suggest that the higher level of salivary thiocyanate in smokers is responsible for the increased rate of endogenous nitrosation of proline in this group compared to the rate in nonsmokers. Nitrosating agents in cigarette smoke do not appear to play a significant role.

Colon cancer and dietary fat, phosphate, and calcium: a hypothesis.

Increased dietary fat was suggested to promote colon cancer by increasing the levels of free ionized fatty acids and bile acids in the colon contents. In the presence of calcium ions the irritating and toxic effects of the free acids on colon epithelial cells could be reduced by being converted to insoluble calcium soaps. The level of supplementary dietary calcium to supply adequate calcium and thus reduce the potential toxicity of dietary fat was considered.

Colonic hyperplasia and hyperproliferation induced by a nutritional stress diet with four components of Western-style diet.

We studied the effects of specific nutritional modifications on colonic epithelial cell proliferation in mice and rats. The nutritional stress diet developed for this study was based on the AIN (American Institute of Nutrition)-76A semisynthetic diet, modified to contain four suggested risk factors of the human Western-style diet: increased fat and phosphate and decreased calcium and vitamin D content. We fed diets to mice and rats for 12 weeks beginning at 3 weeks of age. Hyperplasia developed in both sigmoid and ascending colon of mice and rats with lengthening of colonic crypts. Hyperproliferation developed in the sigmoid colon of mice and rats, and in the ascending colon of rats, with increased [3H]thymidine-labeling of epithelial cells. Thus, in colonic mucosa, the nutritional stress diet, which included risk factors of a Western-style diet, induced changes that occur in carcinogen-induced rodent models and in humans who are at increased risk for colonic neoplasia.

Nuclear aberrations as a short-term test for genotoxicity to the colon: evaluation of nineteen agents in mice.

The genotoxicity of 16 agents including several hydrazines, nitrosamines, aromatic amines, polycyclic hydrocarbons, and other related compounds and three known inhibitors of carcinogenesis was assessed in the murine colonic nuclear aberration assay. Of the seven agents considered positive for colonic DNA damage, five were large bowel carcinogens. All structural analogues of the intestinal carcinogens that are tumorigenic for other organs, with the exception of benzo[a]pyrene, were negative in the colonic nuclear aberration assay as were all noncarcinogens tested. The metabolic inhibitor disulfiram completely inhibited 1,2-dimethylhydrazine-induced colonic nuclear damage, while inhibition was less marked for the antioxidants butylated hydroxyanisole and caffeic acid. The versatility of the assay as an indicator of colonic genotoxicity resulting from carcinogen exposure is discussed.

Calcium, vitamin D, and colon cancer.

Calcium contributes to the progression of epithelial cells through all phases of the proliferative cycle and into stages of cell differentiation; intracellular concentrations of calcium that are required for cell renewal, however, are lower than those required for epithelial-cell differentiation. These effects of calcium are modulated by interactions with 1,25-dihydroxy-vitamin D3, phosphate, and fatty acids, all of which are partly dependent on dietary intake. In rodent models, increased dietary calcium inhibited hyperproliferation of colon epithelial cells induced by increased levels of fatty acids or bile acids present in the colon. When carcinogens induced hyperproliferation of colon epithelial cells the hyperproliferation was decreased by added dietary calcium, and in several animal models the occurrence of carcinogen-induced carcinomas of the colon decreased with increased dietary calcium. A nutritional stress diet, designed to represent human Western dietary intake of calcium, phosphate, vitamin D, and fat, produced hyperproliferation and hyperplasia in the colons of rodents; these effects were reduced by increasing dietary levels of calcium. Decreased levels of ornithine decarboxylase also were reported in human and rodent colon mucosa exposed to increasing levels of calcium. In human subjects at increased risk for familial colon cancer, hyperproliferation of colon epithelial cells was reduced after oral dietary supplementation with calcium. In epidemiological studies, several investigators reported inverse correlations between levels of dietary calcium intake and the incidence of colon cancer. Extrapolation of the data have suggested a protective effect of total calcium intakes above 1500 to 1800 mg/day.

Effects of dietary fat, calcium, and vitamin D on growth and mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene in female Sprague-Dawley rats.

This study was designed to test the influence of dietary calcium and vitamin D levels on the promotional effect of high-fat diets on chemically induced mammary carcinogenesis. In a small preliminary experiment (Experiment A), 40 female Sprague-Dawley rats, 43 days old, were randomly divided into 5 groups (8 rats/group) and fed a semipurified diet containing 3% sunflower seed oil (SF) by weight, 1.5 mg of calcium/kcal and 0.5 IU vitamin D/kcal of diet. After 1 week, each rat was given 2.5 mg of dimethylbenz(a)anthracene by gastric gavage. One week later, the animals were switched to 1 of 4 diets varying in fat (3 or 20% SF by weight), calcium (1.5 or 0.25 mg/kcal), vitamin D (0.5 or 0.05 IU/kcal), and phosphate or to a fifth diet containing 3% SF by weight, 0.1 mg of calcium/kcal and 0.05 IU of vitamin D/kcal. In all 5 diets, calcium:phosphate weight ratios were maintained at 1.2:1. In animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) increased the incidence of mammary lesions from 37 to 75% and the total number of lesions from 4 to 16. A trend toward an increase in lesion weight and total lesion burden was also seen. To confirm these results, the experiment was repeated using the same protocol; 126 rats were divided into 6 groups, treated with dimethylbenz(a)anthracene, and fed the diets as described. A sixth diet was included that contained 20% SF by weight, 0.01 mg of calcium/kcal, and 0.05 IU of vitamin D/kcal. As for Experiment A, in animals fed the high-fat diet, reduction of dietary calcium (1.5 to 0.25 mg/kcal) and vitamin D (0.5 to 0.05 IU/kcal) resulted in an increase in total mammary lesions from 31 to 55, a significant increase in average lesion burden/rat with lesions (1.6 +/- 0.6 to 12 +/- 3 g), and a trend toward increasing weight of lesions. The effect was less obvious in animals fed the low-fat diet where, in both experiments, an increase in the incidence of mammary lesions was observed only when the dietary calcium was reduced from 1.5 to 0.1 mg/kcal. These data suggest that decreasing calcium and vitamin D increase the promoting effects of a high-fat diet on mammary tumorigenesis in the rat.

Labeling index and labeling distribution of cells in esophageal epithelium of individuals at increased risk for esophageal cancer in Huixian, China.

The pattern of proliferation of epithelial cells in esophageal epithelium was studied by means of [3H]deoxythymidine labeling of esophageal epithelium in subjects from Huixian, Henan Province, China, a high-risk geographical region for esophageal cancer. Comparisons were made among patterns of cell proliferation observed in normal esophagus, in hyperplasia, in mild dysplasia, and in moderate dysplasia in a total of 118 subjects. The amount of cell proliferation observed was lowest in normal esophageal epithelium and increased progressively in subjects having hyperplasia, mild dysplasia, and moderate dysplasia. The location of proliferating cells was limited mainly to the base of the esophageal epithelium in normal esophagus, but expanded toward the surface of the esophageal lining in individuals with hyperplasia and dysplasia. The larger total numbers of proliferating cells in the esophageal epithelium and the progressive expansion of the proliferative compartment toward the epithelial surface found in hyperplasia and in dysplasia could both facilitate the screening of subjects for esophageal cancer risk and serve as intermediate biomarkers in prophylactic dietary or pharmacological intervention studies.

Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice.

Curcumin (diferuloylmethane), a yellow pigment that is obtained from the rhizomes of Curcuma longa Linn., is a major component of turmeric and is commonly used as a spice and food-coloring agent. The inhibitory effects of feeding commercial grade curcumin (77% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin) in AIN 76A diet on carcinogen-induced tumorigenesis in the forestomach, duodenum, and colon of mice were evaluated. Administration p.o. of commercial grade curcumin in the diet inhibited benzo(a)pyrene-induced forestomach tumorigenesis in A/J mice, N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumorigenesis in C57BL/6 mice, and azoxymethane (AOM)-induced colon tumorigenesis in CF-1 mice. Dietary commercial grade curcumin was given to mice at: (a) 2 weeks before, during, and for 1 week after carcinogen administration (during the initiation period); (b) 1 week after carcinogen treatment until the end of the experiment (during the postinitiation period); or (c) during both the initiation and postinitiation periods. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of benzo(a)pyrene-induced forestomach tumors per mouse by 51-53% when administered during the initiation period and 47-67% when administered during the postinitiation period. Feeding 0.5-2.0% commercial grade curcumin in the diet decreased the number of N-ethyl-N'-nitro-N-nitrosoguanidine-induced duodenal tumors per mouse by 47-77% when administered during the postinitiation period. Administration of 0.5-4.0% commercial grade curcumin in the diet both during the initiation and postinitation periods decreased the number of AOM-induced colon tumors per mouse by 51-62%. Administration of 2% commercial grade curcumin in the diet inhibited the number of AOM-induced colon tumors per mouse by 66% when fed during the initiation period and 25% when fed during the postinitiation period. The ability of commercial grade curcumin to inhibit AOM-induced colon tumorigenesis is comparable to that of pure curcumin (purity greater than 98%). Administration of pure or commercial grade curcumin in the diet to AOM-treated mice resulted in development of colon tumors which were generally smaller in number and size as compared to the control group of AOM-treated mice. These results indicate that not only did curcumin inhibit the number of tumors per mouse and the percentage of mice with tumors but it also reduced tumor size. Histopathological examination of the tumors showed that dietary curcumin inhibited the number of papillomas and squamous cell carcinomas of the forestomach as well as the number of adenomas and adenocarcinomas of the duodenum and colon.

Enhanced skin carcinogenesis in transgenic mice with high expression of glutathione peroxidase or both glutathione peroxidase and superoxide dismutase.

Female transgenic mice (C57BL/6 x CBA/J)F1 with a 1-fold increase in expression of glutathione peroxidase (GP) or with a 1-fold increase in the expression of GP and a 3-4-fold increase in the expression of superoxide dismutase (SOD) had an enhanced carcinogenic response to initiation by 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). GP- or GP+SOD-transgenic mice that were initiated by a single topical application of 200 nmol of DMBA followed by promotion with 8 nmol of TPA twice weekly for 30 weeks developed an average of 10.9 or 11.0 skin tumors per mouse and a 100% tumor incidence in comparison with the corresponding nontransgenic mice, which had 3.9 tumors per mouse and an 83% tumor incidence. After stopping TPA application, partial skin tumor regression occurred more rapidly in nontransgenic mice than in either type of transgenic mouse. At 10 weeks after termination of TPA treatment, 9-11% of the tumor-bearing transgenic mice and 26% of the tumor-bearing nontransgenic mice had complete regression of their tumors. Histopathological examination of 96 skin papillomas revealed that the area, location, degree of tumor dysplasia, bromodeoxyuridine labeling index, and p53 protein levels were closely intercorrelated. Further analysis indicated that papillomas with the same grade of dysplasia had a higher bromodeoxyuridine labeling index and a greater p53 protein level in GP- or GP+SOD-transgenic mice than those in nontransgenic mice. The data indicated that overexpression of skin antioxidant enzymes GP or GP+SOD, which are enzymes that are believed to protect cells from oxidative damage by scavenging reactive oxygen species, lead to the increased, rather than the decreased, tumorigenesis in a DMBA/TPA two-stage skin carcinogenesis model.

Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice.

In a previous study (Z. Y. Wang et al., Cancer Res., 52: 1162-1170, 1992), we found that administration of a water extract of green tea leaves as the sole source of drinking fluid inhibited ultraviolet B light (UVB)-induced carcinogenesis in SKH-1 mice previously initiated with 7,12-dimethylbenz[a]anthracene (DMBA). In the present study, we compared the effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on UVB-induced skin carcinogenesis in DMBA-initiated SKH-1 mice. A 1.25% water extract of each kind of tea leaf (1.25 g tea leaf/100 ml water) was prepared by passing 4 liters of hot water through 50 g of tea leaves in a Bunn tea brewing machine. The mean concentrations of solids in multiple samples of 1.25% black tea, green tea, decaffeinated black tea, and decaffeinated green tea analyzed during the course of this study were 4.23, 3.94, 3.66, and 3.53 mg/ml, respectively. These concentrations of tea solids are similar to those present in tea brews ingested by humans. Female SKH-1 mice were treated topically with 200 nmol of DMBA, followed 3 weeks later by irradiation with 30 mJ/cm2 of UVB twice weekly for 31 weeks. UVB-induced formation of skin tumors was markedly inhibited by oral administration of 0.63 or 1.25% black tea, green tea, decaffeinated black tea, or decaffeinated green tea as the sole source of drinking fluid 2 weeks prior to and during 31 weeks of UVB treatment. Administration of each of the eight tea preparations not only inhibited the number of tumors, but tumor size was also markedly decreased. Histopathological examination of each tumor showed that oral administration of the eight tea preparations had a marked inhibitory effect on the formation of UVB-induced keratoacanthomas and carcinomas. Administration of 1.25% black tea, green tea, decaffeinated black tea, or decaffeinated green tea inhibited the number of keratoacanthomas per mouse by 79, 78, 73, or 70%, respectively, and the number of carcinomas per mouse was inhibited by 93, 88, 77, or 72%, respectively. In summary, administration of black tea was comparable to green tea as an inhibitor of UVB-induced skin carcinogenesis in DMBA-initiated SKH-1 mice. Oral administration of decaffeinated black tea or decaffeinated green tea also had a marked inhibitory effect on UVB-induced skin carcinogenesis in DMBA-initiated SKH-1 mice, but these tea preparations were slightly less effective than the regular teas at the high dose level.

Modulation of colonic epithelial cell proliferation, histone acetylation, and luminal short chain fatty acids by variation of dietary fiber (wheat bran) in rats.

The effect of increasing amounts of wheat bran (0, 5, 10, 20%) in AIN-76 semisynthetic diet on colonic luminal short chain fatty acids, epithelial cell histone acetylation, and cytokinetics, was studied for 2 weeks in groups of 10 male Sprague-Dawley rats. Luminal contents were removed from the colon at sacrifice, quick frozen, and analyzed for short chain fatty acids by gas-liquid chromatography. Histone acetylation was assessed in cells isolated from the same animals. Cell proliferation was measured after a short pulse in vivo with [3H]thymidine. Colonic luminal butyrate levels were lower in the 0 and 20% fiber groups, and higher in the 5 and 10% fiber groups. In contrast, cell proliferation, as determined by labeling index, was higher in the 0 and 20% fiber groups, and lower in the 5 and 10% fiber groups. This resulted in a significant inverse correlation between luminal butyrate levels and colonic cell proliferation. In addition, there was a positive linear correlation between luminal butyric acid levels and colon epithelial cell histone acetylation. From these data it was concluded that colonic butyrate levels can be modulated by the addition of wheat bran to the diet and that butyrate can modulate DNA synthesis (calculated as labeling index) in the proliferative compartments of colonic crypts. The localization of dividing cells was unchanged and no induction of terminal differentiation was detectable (contrary to what has been observed for transformed cells in culture).

Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis.

Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH-2) is a key enzyme in the formation of prostaglandins and thromboxanes. Cox-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers and suppression of apoptosis in cultured epithelia] cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide. To address the relationship between Cox-2, apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the Apc gene, leading to the development of gastrointestinal adenomas by 110 days of age. Min mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/day) in drinking water. Control Min mice and homozygous C57BL/6J-+/+ normal littermates lacking the Apc mutation (+/+) were fed AIN-76A diet and given tap water to drink. At 110 days of age, all mice were sacrificed, and their intestinal tracts were examined. Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindac-treated Min mice. As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from Min animals revealed increased amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates. Using two different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals. Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E(2) to baseline and restored normal levels of apoptosis. These data suggest that overexpression of Cox-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.

The role of micronutrient deficiency in carcinogenesis.

Nutritional deficiencies are suspected to be contributing factors to several types of human cancers. Studies with laboratory animals have demonstrated that deficiencies in certain nutrients can enhance chemically induced carcinogenesis. In this review, we discuss several possible mechanisms for the involvement of nutritional deficiencies in carcinogenic processes, and note that different severities of deficiency may have varied effects on these processes. The relationship between results from studies with animals and the genesis of human cancer is discussed, and the application of the concept of nutrient density in relating experimental animal diets to human dietary conditions is emphasized. We also discuss in detail several recent studies that potentially may have a great impact on the prevention of human cancer. These include (1) the possible involvement of micronutrient deficiencies in carcinogenesis of the esophagus; (2) the effects of choline/methionine deprivation and calcium supplementation on liver carcinogenesis; and (3) the roles of low-calcium and high-fat intake on development of colon cancer. The possible mechanistic link between teratogenesis and carcinogenic processes is noted.

Colonic hyperproliferation induced in rats and mice by nutritional-stress diets containing four components of a human Western-style diet (series 2).

In a previous study colonic hyperplasia and hyperproliferation were induced in mice and rats by a nutritional-stress diet, based on the AIN-76A semisynthetic diet modified to contain four suggested high-risk components of the human Western-style diet: increased fat and phosphate and decreased calcium and vitamin D contents. In this study the effect of raising calcium alone to near the median level (0.22 mg/kcal) and to a high level (1.3 mg/kcal), comparable to adult human dietary intake, was tested in mice and rats while retaining the three other high-risk components. With median calcium intake the nutritional-stress diet induced hyperproliferation of epithelial cells in colonic crypts, with increased numbers of proliferating cells in crypt columns in sigmoid colon of mice (P less than 0.001) and rats (P = 0.02) and in the ascending colon of mice (P = 0.01). With high calcium intake, hyperproliferation was reduced almost to control amounts in the presence of unchanged fat, phosphate, and vitamin D.

Stability of vitamin B12 in the presence of ascorbic acid.

Experiments were performed in two independent laboratories, each using their own meal preparations which were exactly similar in composition to the meals described by Herbert and Jacob (J. Am. Med. Assoc. 230:241, 1974), in order to check their report that incubating meals (portions of daily food intake by man) of "modest" or "high" vitamin B12 content with increasing levels of added L-ascorbic acid (vitamin C) produced increasing destruction of vitamin B12. The present studies were performed with standardized and official methods. Vitamin B12 was determined microbiologically and by radioassay method. The results showed that 1) the vitamin B12 contents of these meals were in general agreement with values calculated from the literature for the foods involved, 2) the values obtained were manyfold higher than those reported by Herbert and Jacob, and 3) there was no deleterious effect of added ascorbic acid on the vitamin B12 content of meals, contrary to their published results.

Calcium and carcinogenesis of the mammary gland.

Effects of dietary calcium on mammary carcinogenesis in rats were investigated because of evidence that calcium counteracts the promotion of colon cancer by dietary fat and because experimental diets for rats normally contain higher amounts of calcium and vitamin D than do human diets. Our earlier experiments indicated that yields of tumors induced in young, Sprague-Dawley rats by 7,12-dimethylbenz(a)-anthracene (DMBA) were higher when dietary calcium, phosphate, and vitamin D were decreased. Results of an experiment in which dietary amounts of calcium, phosphate, and vitamin D were varied independently suggested that phosphate and vitamin D have interactive effects with calcium. Another experiment in which dietary vitamin D alone was varied provided evidence that higher amounts inhibited tumorigenesis in the presence of low amounts of calcium and phosphate but the results with a high-calcium and -phosphate diet were inconclusive. The findings suggest that low amounts of dietary calcium and vitamin D and high amounts of phosphate increase susceptibility to DMBA-induced mammary neoplasia.

Squalene, olive oil, and cancer risk: a review and hypothesis.

Epidemiological studies of breast and pancreatic cancer in several Mediterranean populations have demonstrated that increased dietary intake of olive oil is associated with a small decreased risk or no increased risk of cancer, despite a higher proportion of overall lipid intake. Experimental animal model studies of high dietary fat and cancer also indicate that olive oil has either no effect or a protective effect on the prevention of a variety of chemically induced tumors. As a working hypothesis, it is proposed that the high squalene content of olive oil, as compared to other human foods, is a major factor in the cancer risk-reducing effect of olive oil. Experiments in vitro and in animal models suggest a tumor-inhibiting role for squalene. A mechanism is proposed for the tumor-inhibitory activity of squalene based on its known strong inhibitory activity of beta-hydroxy-beta-methylglutaryl-CoA reductase catalytic activity in vivo, thus reducing farnesyl pyrophosphate availability for prenylation of the ras oncogene, which relocates this oncogene to cell membranes and is required for the signal-transducing function of ras.

A randomized double-blind intervention study on the effect of calcium supplementation on esophageal precancerous lesions in a high-risk population in China.

To determine whether dietary calcium supplementation affects esophageal precancerous lesions, 200 subjects with esophageal lesions in a high-risk area for esophageal cancer in China (Huixian, Henan) were randomly divided into 2 groups (100 subjects/group). Subjects in one group received an oral supplementation of calcium carbonate tablets (1200 mg of calcium daily), and subjects in the other group received placebo pills for 11 months. At the entry and the end of the trial, esophagoscopy was performed, and 2 or 3 biopsy specimens were taken from the middle and lower thirds of the esophagus and from macroscopic lesions, if any, of each subject for histopathology and cell proliferation analysis with deoxythymidine labeling. In comparison to normal epithelium, increased proliferative compartment size was observed in epithelia with hyperplasia or dysplasia. After the intervention, the percentage of individuals with "normal epithelium," "basal cell hyperplasia," "basal cell hyperplasia II," and "basal cell hyperplasia III and dysplasia" were 44, 31, 13, and 11% in the calcium group and 35, 39, 17, and 6% in the placebo group, respectively. The labeling index was 0.046 in the calcium group and 0.044 in the placebo group. After the intervention, the labeling index in basal cell layers 1 to 5, the major zone of cell proliferation, fell 38% in the calcium group and 44% in the placebo group from before the intervention. Therefore, in this study, calcium supplementation was not shown to have beneficial effects in alleviating precancerous lesions and abnormal cell proliferation patterns.

Calcium inhibits the damaging and compensatory proliferative effects of fatty acids on mouse colon epithelium.

Intrarectal instillations of the fatty acids (FA), lauric, linoleic or oleic acids induce inflammation and superficial lysis of the colon epithelium. This reaction is followed by increases in colonic mitotic activity and the number of cells engaged in DNA synthesis in compensatory regeneration for the cells that were lost. This explains, in part, the promotional effect of dietary fat in carcinogenesis. Concomitant oral administration of calcium salts, as CaCO3, largely reduced the mitogenic effects of fatty acids on colon epithelium, presumably by forming biologically inert calcium soaps. Calcium soap formation of dietary fatty acids may be one natural mechanism by which colon epithelium cells are protected hence reducing the impact of dietary fat on carcinogenesis for this organ.

Butyrate as a differentiating agent: pharmacokinetics, analogues and current status.

The field of butyrate-induced differentiation of neoplastic and non-neoplastic cells is reviewed and possible clinical correlations considered with regard to butyrate, butyrate prodrugs and butyrate analogues. These topics are discussed from the point of view of the concentrations required in vitro for biologic effect, and likely pharmacokinetic behavior in vivo.