Ranking chemopreventive agents on rat colon carcinogenesis.
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Animals↗
Biomedical subjects
S Taché
Publications and source records attributed to S Taché.
Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice.
Polyethylene-glycol (PEG) is a strong inhibitor of colon cancer in rats, and the most potent suppressor of aberrant crypt foci. 9 PEG-like block copolymers were tested in rodents, after an azoxymethane injection. Dietary pluronic F68 led to a 98.6% reduction in the number of aberrant crypt foci in a first rat study (P< 0.0001). Next 3 studies confirmed this pluronic efficacy in rats and mice. This non-toxic laxative seems roughly 5 times more potent than PEG for chemoprevention.
Animals↗
The master's in public health: a better preparation for understanding the health care system.
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Delivery of Health Care↗
Consistent and fast inhibition of colon carcinogenesis by polyethylene glycol in mice and rats given various carcinogens.
We have previously shown that dietary polyethylene-glycol (PEG) suppresses the occurrence of azoxymethane-induced cancers in an accelerated rat model of colon carcinogenesis. To determine the consistency of this preventive effect, we carried out a long-term study in rats fed the standard American Institute of Nutrition 1976 diet, and 7 short-term prevention studies in rodents. A total of 337 F344 rats, 20 Sprague Dawley rats, and 40 OF1 mice were all given initiating dose(s) of colon carcinogen, and were randomly allocated to experimental groups 7 d later. Treated groups received drinking water containing 5% PEG. After 30 or 162 d, the animals were examined for aberrant crypt foci or tumors in the colon. After two 20 mg/kg azoxymethane injections, the number of F344 rats with colon tumor was lower in rats receiving PEG for 162 d than in carcinogen-injected controls, 5/21 versus 25/27 (P < 0.0001). PEG-fed rats had no invasive cancer, and 10 times fewer colon tumors than controls (0.3+/-0.1 and 3.1+/-0.5 respectively, P < 0.0001). A three-day PEG treatment was sufficient to halve the number of azoxymethane-induced aberrant crypt foci in F344 rats (P = 0.0006). After 16 d of treatment, PEG-fed rats had five times fewer foci than controls (21+/-14 and 100+/-23 respectively, P < 0.0001), but the inhibition was reversible in part when treatment was discontinued. Aberrant crypt foci initiated by N-methyl-N-nitrosourea intra-rectally (40 mg/kg) or by 2-amino-3,4-dimethylimidazo(4,5-f)quinoline p.o. (2 x 200 mg/kg) were suppressed by PEG (P < 0.0001 and P = 0.003 respectively). PEG was active in F344 rats, in Sprague Dawley rats (P = 0.0005), and in OF1 mice (P = 0.001). PEGs with MW between 3350 and 12000 (but not PEG 400), and PEG 8000 from five suppliers, markedly inhibited azoxymethane-induced aberrant crypt foci (all P < 0.01). The prevention was stronger in rats fed a high-fat diet (P < 0.0001) than in rats fed a rodent chow (P = 0.02). PEG was thus a fast, consistent, and potent inhibitor of early colonic precursor lesions. Moreover, PEG is one of the most potent inhibitors of colon tumor in the standard rat model. Since PEG has no known toxicity in humans, we think it should be tested as a chemopreventive agent in a clinical trial.
Animals↗
Carrageenan gel and aberrant crypt foci in the colon of conventional and human flora-associated rats.
Carrageenans (CAR) are sulfated polymers from seaweed used as gelling agents in foods. Chemical carcinogen induction of tumors in the colon of rats is enhanced by CAR. We speculated that gut microflora is involved in this effect. We thus studied the initiating and promoting effects of undegraded CAR-kappa (345,000 mol wt) in conventional rats and in germ-free rats associated with a human fecal flora. The initiating effect of CAR was studied by scoring aberrant crypt foci (ACF) in the colon of Fischer 344 rats given CAR (10% in water). The promoting effect of CAR was studied by comparing the multiplicity of ACF (number of crypts/focus) in rats receiving pure water or CAR (0.25% and 2.5% in water) for 100 days, starting 7 days after azoxymethane initiation (1 dose of 20 mg/kg i.p.). Duplicate studies were conducted in conventional rats and in human flora-associated rats maintained in isolators. Results show that CAR did not initiate ACF. In conventional rats, the 2.5% CAR gel promoted the growth of ACF: 2.98 +/- 0.29 and 3.44 +/- 0.48 crypts/ACF in control and treated rats, respectively (p < 0.02). The 0.25% CAR gel did not promote ACF. CAR can thus enhance intestinal tumors in this rat model, but only at a high dose level. In contrast, we did not observe any promoting effect of the administration of the 2.5% CAR gel in human flora-associated rats: 2.81 +/- 0.18 and 2.78 +/- 0.38 crypts/ACF in control and treated rats, respectively (p = 0.80). The specific microflora of rats, but not the human gut flora, might be involved in colon tumor enhancement by CAR.
Animals↗
Endogenous N-nitroso compounds, and their precursors, present in bacon, do not initiate or promote aberrant crypt foci in the colon of rats.
Processed meat intake is associated with increased risk of colorectal cancer. This association may be explained by the endogenous formation of N-nitroso compounds (NOC). The hypothesis that meat intake can increase fecal NOC levels and colon carcinogenesis was tested in 175 Fischer 344 rats. Initiation was assessed by the number of aberrant crypt foci (ACF) in the colon of rats 45 days after the start of a high-fat bacon-based diet. Promotion was assessed by the multiplicity of ACF (crypts per ACF) in rats given experimental diets for 100 days starting 7 days after an azoxymethane injection. Three promotion studies were done, each in 5 groups of 10 rats, whose diets contained 7%, 14%, or 28% fat. Tested meats were bacon, pork, chicken, and beef. Fecal and dietary NOC were assayed by thermal energy analysis. Results show that feces from rats fed bacon-based diets contained 10-20 times more NOC than feces from control rats fed a casein-based diet (all p < 0.0001 in 4 studies). In bacon-fed rats, the amount of NOC input (diet) and output (feces) was similar. Rats fed a diet based on beef, pork, or chicken meat had less fecal NOC than controls (most p < 0.01). No ACF were detected in the colon of bacon-fed uninitiated rats. After azoxymethane injection, unprocessed but cooked meat-based diets did not change the number of ACF or the ACF multiplicity compared with control rats. In contrast, the bacon-based diet consistently reduced the number of large ACF per rat and the ACF multiplicity in the three promotion studies by 12%, 17%, and 20% (all p < 0.01). Results suggest that NOC from dietary bacon would not enhance colon carcinogenesis in rats.
Animals↗
Polyethylene-glycol suppresses colon cancer and causes dose-dependent regression of azoxymethane-induced aberrant crypt foci in rats.
Dietary polyethylene-glycol (PEG) 8000, a nonfermented polymer laxative, strongly suppresses azoxymethane-induced aberrant crypt foci (ACF) in the colon of rats, as shown in a previous study (D. E. Corpet et al., Carcinogenesis (Lond.), 20: 915-918, 1999). In the present study, we tested the effect of PEG administered during either initiation or postinitiation, the dose-response effect of PEG, the regressive effect of PEG on established ACF, and the preventive effect of PEG on colon cancers in rats. The general design was to initiate carcinogenesis in F344 rats by a single injection of azoxymethane (20 mg/kg) and to randomize the animals 7 days later to AIN-76 diets containing 5% PEG or no PEG (control). At termination, ACF and tumors were scored blindly by a single observer. The administration of 5% PEG for 32 days to groups of 10 female rats in either food or drinking water reduced the number of ACF by a factor of 8 (P = 0.0002) and reduced the number of large ACF by a factor of 20-30 (P = 0.002). No protection was afforded when PEG was given only during the initiation phase. Diets containing 0%, 0.5%, 2%, or 5% PEG fed for 35 days to four groups of male rats inhibited ACF in a dose-dependent manner (P < 0.0001). The administration of a 5% PEG diet for 41 days, starting 42 days after carcinogen injection, led to a 73% decrease in the number of ACF (P < 0.0001). Dietary PEG thus caused the regression of established ACF. Macroscopic tumors were evaluated by histology in rats that had been fed a high-fat diet containing cooked casein to promote tumor growth for 81 days. In this accelerated model of carcinogenesis, dietary PEG suppressed the occurrence of colon adenomas and carcinomas: the incidence of tumors decreased from 70% to 10% (P = 0.005); and the multiplicity decreased from 2.1 to 0.1 tumor(s)/rat (P = 0.003). No cancer was detected in the PEG-fed rats. Taken together, these results suggest that PEG could be a potent anticancer agent in the postinitiation phase of carcinogenesis. Because PEG is a substance that is generally recognized as safe (GRAS list, Food and Drug Administration), its cancer-preventive features could be tested in humans.
Animals↗
Glycemic index, nutrient density, and promotion of aberrant crypt foci in rat colon.
We speculated that a diet with a high glycemic index (GI) or a diet with a low nutrient density (nutrient-to-calorie ratio) would enhance colon carcinogenesis, presumably via increased insulin resistance. Forty-eight Sprague-Dawley (SD) rats received an azoxymethane injection (20 mg/kg) and were randomized into five groups given an AIN-76 diet containing 1) 65% starch by weight, 2) 65% glucose (GI = 100), 3) 65% fructose (GI = 23), 4) 82% starch, or 5) 39% oil and 39% sucrose. The nutrient density of Diets 4 and 5 was one-half that of Diets 1-3. Promotion was assessed by the multiplicity (number of crypts) of aberrant crypt foci (ACF), an early marker of colon carcinogenesis. Insulin resistance was estimated by the FIRI index (blood insulin x blood glucose), by plasma triglycerides, and by visceral fat. To confirm the results in another rat strain, the experiment was duplicated in 48 Fischer (F344) rats. Results show that 1) the ACF multiplicity was not different in glucose- and fructose-fed rats (p > 0.7): diets with contrasting GI had the same effect on ACF growth; 2) diets of low nutrient density increased visceral fat (p < 0.05) but reduced the ACF size in F344 rats (p < 0.001, no reduction in SD rats); and 3) indirect insulin resistance markers (FIRI index, blood triglycerides, and visceral fat) did not correlate with ACF multiplicity. These results do not support the hypothesis that diets with a high GI or low nutrient density or diets that increase some indirect insulin resistance markers can promote colon carcinogenesis in F344 or SD rats.
Adipose Tissue↗
Effect of meat (beef, chicken, and bacon) on rat colon carcinogenesis.
High intake of red meat or processed meat is associated with increased risk of colon cancer. In contrast, consumption of white meat (chicken) is not associated with risk and might even reduce the occurrence of colorectal cancer. We speculated that a diet containing beef or bacon would increase and a diet containing chicken would decrease colon carcinogenesis in rats. One hundred female Fischer 344 rats were given a single injection of azoxymethane (20 mg/kg i.p.), then randomized to 10 different AIN-76-based diets. Five diets were adjusted to 14% fat and 23% protein and five other diets to 28% fat and 40% protein. Fat and protein were supplied by 1) lard and casein, 2) olive oil and casein, 3) beef, 4) chicken with skin, and 5) bacon. Meat diets contained 30% or 60% freeze-dried fried meat. The diets were given ad libitum for 100 days, then colon tumor promotion was assessed by the multiplicity of aberrant crypt foci [number of crypts per aberrant crypt focus (ACF)]. The ACF multiplicity was nearly the same in all groups, except bacon-fed rats, with no effect of fat and protein level or source (p = 0.7 between 8 groups by analysis of variance). In contrast, compared with lard- and casein-fed controls, the ACF multiplicity was reduced by 12% in rats fed a diet with 30% bacon and by 20% in rats fed a diet with 60% bacon (p < 0.001). The water intake was higher in bacon-fed rats than in controls (p < 0.0001). The concentrations of iron and bile acids in fecal water and total fatty acids in feces changed with diet, but there was no correlation between these concentrations and the ACF multiplicity. Thus the hypothesis that colonic iron, bile acids, or total fatty acids can promote colon tumors is not supported by this study. The results suggest that, in rats, beef does not promote the growth of ACF and chicken does not protect against colon carcinogenesis. A bacon-based diet appears to protect against carcinogenesis, perhaps because bacon contains 5% NaCl and increased the rats' water intake.
Adipose Tissue↗
Carborundum, a bulk similar to dietary fibers but chemically inert, does not decrease colon carcinogenesis.
Dietary fibers might lower the risk of colorectal cancer, maybe because of their bulking effect. We tested the protection afforded by an inert bulk against carcinogenesis. Thirty rats received an azoxymethane injection and were allocated to a control diet, or to a diet supplemented with 10% carborundum. After 100 days the colons were scored for aberrant crypt foci. Compared to controls, the fecal weight was doubled in carborundum-fed rats (P < 0.001), but the aberrant crypt foci multiplicity was not changed (P = 0.92). The results do not support the hypothesis that intestinal dilution by an inert bulk can protect against colon cancer.
Alkaline Phosphatase↗
Carrageenan given as a jelly, does not initiate, but promotes the growth of aberrant crypt foci in the rat colon.
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Animals↗
Colon tumor promotion: is it a selective process? Effects of cholate, phytate, and food restriction in rats on proliferation and apoptosis in normal and aberrant crypts.
Promotion would suppose the selection of initiated cells. We tested the selection of aberrant crypt cells by cholic acid, a colon cancer promoter, and the effect of protectors, phytate and food restriction. After an azoxymethane injection, rats were allocated to a control diet, or to supplements of cholic acid, sodium phytate, or to a 50% food restriction. The proliferation and apoptosis of 1200 crypts were assessed, after immuno-staining for BrdU. Cholic acid increased the proliferation of aberrant crypts but not of normal crypts. Phytate and food restriction decreased the proliferation of normal crypts, but not of aberrant crypts. Apoptosis was not affected by diets. Results support the hypothesis that cholic acid can select initiated cells in the colon.
Analysis of Variance↗
Insulin injections promote the growth of aberrant crypt foci in the colon of rats.
The main objective of the present study was to test the hypothesis that exogenous insulin would enhance colon carcinogenesis. Thirty-six female Fischer 344 rats were fed ad libitum a low-fat rodent chow and given a single azoxymethane injection (20 mg/kg); one week later, they were randomized into two groups. Control rats were given a subcutaneous saline injection, 5 days/wk, and experimental rats were given Ultralente bovine insulin (20 U/kg). The promoting effect of insulin injections was assessed by the multiplicity (number of crypts) of aberrant crypt foci after 100 days of treatment (72 injections). The rats given insulin ate more and were heavier than controls (215 +/- 11 vs. 182 +/- 7 g, p < 0.001). Insulin injections also increased the amount of abdominal fat, plasma triglycerides, and insulinemia and decreased blood glucose (all p < 0.05). The number of aberrant crypt foci was the same in both groups, but their multiplicity was significantly increased by the insulin injections (2.8 +/- 0.3 vs. 2.5 +/- 0.2 crypt/focus in controls, p = 0.007). In addition, the proportion of sialomucin-producing foci was higher in insulin-injected rats than in controls (p = 0.04). These data show that exogenous insulin can promote colon carcinogenesis in rats and suggest that life-style and diets leading to low blood insulin might protect humans against colorectal cancer.
Animals↗