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PubMed2000

ras p21 Isoprenylation inhibition induces flat colon tumors in Wistar rats.

PURPOSE: The effect of pravastatin, an inhibitor of ras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associated ras p21 in colon tumors. CONCLUSIONS: These findings suggest that the ras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.

Adenocarcinoma↗
PubMed1987

Elevated plasma enteroglucagon alone fails to alter distal colonic carcinogenesis in rats.

The effect of physiologic increases of plasma enteroglucagon, induced by massive bypass or resection of small bowel, on large bowel cell turnover and carcinogenesis was studied in rats in which the distal colon was isolated as a mucous fistula. After injections of azoxymethane, either 85% end-to-side jejunoileal bypass, 85% jejunoileal resection, or sham bypass was performed. Controls underwent colonic transection and resuture, azoxymethane treatment, and then sham bypass. Thirty weeks later the plasma enteroglucagon level had almost trebled after jejunoileal bypass (p less than 0.001) and almost doubled after jejunoileal resection (p less than 0.002) when compared with sham bypass; sham values did not differ from controls. The median number of tumors per rat in the distal (defunctioned) colon fell from 2 to 0 (p less than 0.05). Segmental weight fell by 45% (p less than 0.001) and crypt cell production rate by 75% (p less than 0.001). Neither tumor yield nor adaptation was affected by jejunoileal bypass or jejunoileal resection. Plasma enteroglucagon has no effect on colonic cell turnover or carcinogenesis in the absence of luminal content.

Animals↗
PubMed1995

Regional chemoprevention of carcinogen-induced tumors in rat colon.

BACKGROUND & AIMS: Rat colon neoplasms are distributed 60% in the distal colon (DC) and 40% in the proximal colon (PC), similar to distribution of colon cancers in the industrialized world. The effects of chemopreventive agents that affect colon tumor incidence on the distribution of colon tumors were studied. METHODS: Colon tumor distribution, numbers, and volumes were measured in the DC and PC of rats administered azoxymethane (15 mg/kg subcutaneously 2x) as an initiating agent and fed diets containing various chemopreventive agents. RESULTS: In control rats, azoxymethane-induced tumor incidence in the DC exceeded that in the PC, but tumor volume was greater in the PC than the DC. Ellagic acid showed no chemopreventive effect and maintained the PC-DC colon tumor gradient. Oltipraz, a modestly effective chemopreventive agent, principally reduced the incidence of DC tumors. DL-d-difluoromethylornithine also greatly altered tumor number in the DC compared with the PC. In contrast, piroxicam (400 ppm) reduced PC tumors by 82% but DC tumors only by 57%. With all regimens, tumor volume remained greater in the PC than the DC. CONCLUSIONS: Chemopreventive agents have a selective regional effect on colon tumorigenesis in the rat. Elucidation of the mechanism for these differences may help clarify the modes of action of chemopreventive agents in colon cancer.

Animals↗
PubMed1985

Lack of genetic and in vitro metabolic activity of potently carcinogenic azoxyalkanes.

4 carcinogenic azoxyalkanes (azoxymethane, azoxymethane and the 2 mixed methyl-ethyl compounds) were examined for activity in the Salmonella histidine reversion assay and in a lambda-lacZ prophage induction assay. Because azoxyalkanes are isomeric with nitrosodialkylamines, and might be expected to generate the same active intermediates, their biological activity was investigated under conditions which would allow direct comparison with these well-studied carcinogens. However, none of the azoxyalkanes, which are liver carcinogens, showed significant activity in either microbial assay in the presence of liver S9. In addition, metabolism studies with liver microsomes or hepatocytes indicated that the compounds were metabolized only to a small extent, if at all, under the conditions examined. This inactivity of the azoxyalkanes contrasts with the considerable activity in these assays - and the substantial metabolism - of the isomeric nitrosodialkylamines, also liver carcinogens. These results suggest that the carcinogenic action of azoxyalkanes proceeds through alternative metabolic pathways that are not adequately modeled by the assays and in vitro conditions used here.

Animals↗
PubMed1985

The metabolism and cellular interactions of some aliphatic nitrogenous carcinogens.

The alkylation of nucleic acids of the liver of rats and Syrian hamsters was measured in relation to carcinogenesis by a number of nitrosamines and azoxyalkanes, most of which induce tumors of the liver in both species following chronic treatment. Two compounds, nitroso-2,6-dimethylmorpholine and nitrosobis(2-hydroxypropyl)amine were not liver carcinogens in rats, but did induce liver tumors in hamsters; there was much less alkylation by these compounds in the rat than in the hamster. In both rats and hamsters, azoxymethane produced a greater extent of alkylation, both at N-7 and O-6 guanine, than did nitrosodimethylamine, although the former is no more potent than the latter as a carcinogen in either species. Both methyl groups of azoxymethane gave rise to N-7 methylation. Nitrosobis(2-oxopropyl)amine (BOP) and nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) produced considerable methylation of liver nucleic acids in both species, comparable with that by nitrosodimethylamine, and they induce liver tumors in both rats and hamsters. However, in male rats the extent of alkylation by BOP was much smaller than in females and no O-6-methylation was detected in the former; this correlates with the failure of BOP to induce liver tumors in male rats by gavage, whereas liver tumors are induced in females.

Alkylation↗
PubMed2005

Predisposition to colorectal cancer in rats with resolved colitis: role of cyclooxygenase-2-derived prostaglandin d2.

Colitis markedly increases the risk of developing colon cancer, but the underlying mechanisms are not fully understood. In a rat model of colitis, alterations in epithelial secretion, proliferation, and barrier function persist long after healing has occurred. In the present study, we examined whether rats that have recovered from a bout of colitis are more susceptible to preneoplastic lesions and whether this susceptibility is mediated by cyclooxygenase (COX)-2-derived prostaglandin (PG) D2. Colitis was induced by intracolonic administration of trinitrobenzenesulfonic acid. Six weeks later, weekly treatment with the carcinogen azoxymethane was initiated. Postcolitis rats exhibited significantly more aberrant crypt foci after azoxymethane treatment than controls. The postcolitis rats also exhibited markedly increased colonic PGD2 synthesis and elevated COX-2, H-PGD synthase, and beta-catenin expression. Treatment for 1 week with a selective COX-2 inhibitor or with a selective PGD2 receptor (DP1) antagonist significantly reduced susceptibility of postcolitis rats to aberrant crypt foci development, beta-catenin expression, and mucosal thickness. The results from this animal model suggest that prolonged elevation of COX-2-derived PGD2 synthesis after resolution of colitis may contribute significantly to colitis-associated increases in colon cancer incidence. PGD2 may therefore represent a rational target for therapies directed at reducing the incidence of colitis-associated colorectal cancer.

Animals↗
PubMed1995

Protective role of lactulose in intestinal carcinogenesis.

Primary bile acids are converted to carcinogenic secondary bile acids by colonic bacteria when the colonic pH is high. Therefore acidification of the luminal contents may reduce the cancer risk. The ability of lactulose to reduce colonic pH, secondary bile acid production, mucosa crypt cell production rate and tumour formation was measured in a rat model of intestinal carcinogenesis. Eighty Wistar rats were divided into four groups receiving normal diet alone or with lactulose, azoxymethane or both azoxymethane and lactulose. The addition of lactulose was associated with a significant fall in small intestinal and colonic pH. Lactulose was associated with a sharp rise in the secondary to primary bile acid ratio. The crypt cell production rate fell significantly with lactulose. The addition of lactulose was associated with a significantly reduced tumour yield in small intestine but not in colon. Lactulose therefore can reduce this is of no value in humans at risk of developing colorectal carcinoma.

Acid-Base Imbalance↗
PubMed2002

Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.

BACKGROUND: Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis. METHODS: We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H.pylori (ATCC 43504 strain, CagA+ and VacA+) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis. RESULTS: Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H.pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H.pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates. CONCLUSIONS: Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.

Animals↗
PubMed1996

Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors.

BACKGROUND & AIMS: Multiple studies show that continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the risk of colon cancer in humans and carcinogen-treated rodents. One target for NSAIDs is cyclooxygenase (COX), and two isoforms of this enzyme have been identified: COX-1 and COX-2. The present study was undertaken to determine if there is differential expression of COX in colonic tumors in azoxymethane-treated rats. METHODS: COX-1 and COX-2 messenger RNA levels were determined by Northern blot analysis of total RNA isolated from colonic tumors and normal adjacent mucosa. COX-2 protein levels were determined by Western blotting analysis. Quantitation of relative band densities was performed using standard densitometry scanning techniques. RESULTS: There was a marked increase in COX-2 RNA levels in six of six colonic tumors compared with paired normal mucosa. In contrast, there was equivalent intensity of the COX-1 RNA transcript between the normal mucosa and tumor in all of the specimens examined. Western blotting analysis showed an increase in the level of the COX-2 protein in four of five of the colonic tumor samples. CONCLUSIONS: COX-2 but not COX-1 gene expression is markedly elevated in most colonic tumors examined in azoxymethane-treated rodents. COX-2 may provide a target for chemopreventive strategies for colorectal cancer.

Animals↗
PubMed1995

Lack of aberrant crypt promotion and of mutagenicity in extracts of cooked casein, a colon cancer-promoting food.

Dietary casein cooked at 180 degrees C promotes the growth of aberrant crypt foci and colon cancer in rats initiated with azoxymethane. We speculated that promotion was due to a product that could be extracted by a solvent, such as 5-hydroxymethyl-2-furaldehyde (HMF), with tumor- promoting activity or the carcinogenic heterocyclic aromatic amines (HAA). This hypothesis was tested by extracting cooked casein with solvents and water. The extracts were then 1) assayed by high-performance liquid chromatography for HMF and HAA, 2) measured for mutagenicity on a frame-shift-sensitive strain of Salmonella typhimurium, and 3) fed for 100 days to azoxymethane-initiated rats to test the promoting effect on aberrant crypt foci. Data show that 1) no HMF or HAA was detected in cooked casein, 2) no mutagenicity was detected on strain TA98, with or without metabolic activation, and 3) promotion was not associated with the extracts but with the cooked casein residue. Therefore the promotion by cooked casein would not appear to be associated with a product that can be extracted by solvents.

Animals↗
PubMed1997

Relationship among colonocyte proliferation, differentiation, and apoptosis as a function of diet and carcinogen.

To determine the relationship among colonocyte proliferation, differentiation, and apoptosis as a function of fiber and carcinogen, we conducted a 2 x 2 factorial design study with two fibers (pectin or cellulose) and two injection protocols (azoxymethane or saline) in male Sprague-Dawley rats. Rats were killed six weeks after the injections, and in vivo cell proliferation was measured by incorporation of bromodeoxyuridine into DNA, differentiation by binding of the lectin Dolichos biflorus agglutinin, and apoptosis by immunoperoxidase detection of digoxigenin-labeled genomic DNA. In the proximal colon, pectin decreased differentiation and apoptosis, resulting in a greater number of cells per crypt column. In the distal colon, pectin increased cell proliferation, resulting in more crypts per millimeter of colon and a greater number of surface cells. Azoxymethane increased cell proliferation and decreased differentiation and apoptosis in the proximal and the distal colon. This resulted in a greater number of surface cells proximally and more crypts per millimeter of colon distally. These results illustrate the importance of considering all three parameters (proliferation, differentiation, and apoptosis) when evaluating neoplastic growth.

Animals↗
PubMed1998

Comparative effects of secondary bile acids, deoxycholic and lithocholic acids, on aberrant crypt foci growth in the postinitiation phases of colon carcinogenesis.

The objective of this study was to investigate the effect of deoxycholic (DCA) and lithocholic (LCA) acids on the postinitiation phases of colon cancer. Male Sprague-Dawley rats (n = 170) were injected with azoxymethane (2 injections at 15 mg/kg body wt sc given 1 wk apart) and fed a control (CON) AIN-93 diet. Two weeks after the second azoxymethane injection, 10 animals were killed and aberrant crypt foci (ACF) were enumerated. The remaining animals were randomly assigned to four diet groups: 1) CON, 2) DCA, 3) LCA, and 4) high fat (HF, a positive control group). Bile acid diets consisted of 0.2% by weight DCA or LCA; HF diets consisted of 20% fat (5% soybean oil + 15% beef tallow by weight). Animals were killed at Weeks 3, 12, and 20 (from 1st carcinogen injection), and number and growth features of ACF and adenomatous lesions were enumerated in the colon. At Week 12, ACF number and small, medium, and large (1-3, 4-6, and > or = 7 crypts/focus, respectively) ACF were higher in the HF group than in the DCA, LCA, and CON groups (p < or = 0.05). By Week 20, ACF number and small, medium, and large ACF were similar in the LCA and HF groups, whereas the response was similar in the DCA and CON groups. Average crypt multiplicity was higher in the HF and LCA groups than in the DCA and CON groups (p < or = 0.05). Microadenoma (MA) incidence was higher in the HF group than in the CON and LCA groups (p < or = 0.05). Regional distribution patterns for ACF number were similar to MA and tumor distribution patterns within the CON, DCA, and HF groups. In the LCA group, ACF number and MA showed a proximal predominance in regional distribution, whereas tumors showed a distal predominance. HF diets provided the most stimulatory environment, immediately enhancing the number and growth of ACF and MA incidence. In conclusion, HF and LCA diets exerted distinct effects on postinitiation phases of colon cancer, whereas the DCA diet did not.

Animals↗
PubMed1998

Prevention of precancerous colonic lesions in rats by soy flakes, soy flour, genistein, and calcium.

The main purpose of this research was to determine whether diets containing soy products would inhibit the early stages of azoxymethane-induced colon cancer in F344 rats. Additional objectives were to determine whether feeding starch instead of sucrose, feeding additional calcium (0.5% compared with 0.1%), or feeding a low-fiber powdered enteral formula would influence early colon carcinogenesis. Colon cancer was initiated with 2 injections of azoxymethane (15 mg/kg body wt) and a 12-wk dietary treatment period was started 1 wk after the second injection. Precancerous colon lesions were assessed as foci with aberrant crypts (FAC). The mean numbers of FAC were 133 [soy concentrate (low concentration of phytochemicals)], 111 (starch substituted for sucrose), 98 [full-fat soy flakes (whole soybeans)], 87 (defatted soy flour), 77 (0.015% genistein), and 70 (0.5% Ca). The soy flour and full-fat soy flake diets contained 0.049% genistein derivatives (primarily glycosides), but were less effective in inhibiting the formation of FAC than the diet containing 0.015% genistein (as the aglycone). Eating soybeans and soy flour may reduce the early stages of colon cancer.

Animals↗
PubMed1998

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer.

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.

Animals↗
PubMed1995

Increased N-myristoyltransferase activity observed in rat and human colonic tumors.

BACKGROUND: Colorectal cancer is one of the leading causes of cancer death in North America. Since treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents, it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs and inhibit the development or progression of this disease. Modification of proteins by myristoylation has been recognized as important in the function of various viral, oncogenic, and signal-transduction proteins and thus has been proposed as a target for chemotherapeutic drug design. However, the activity of the enzyme that catalyzes this modification, N-myristoyltransferase, has not been investigated in cancer relative to normal tissue. PURPOSE: The purpose of this study was twofold: 1) to investigate the activity of N-myristoyltransferase in azoxymethane-induced rat colonic cancer tissue compared with normal and normal-appearing rat colonic tissue and 2) to determine if similar differences would be observed in a small sample of human colonic tumors. METHODS: N-Myristoyltransferase activity was determined in 45 colonic tissue specimens from Sprague-Dawley rats--10 given injections of the colon carcinogen, azoxymethane, and three untreated. Tissue specimens included 35 colonic tumors of varying pathologic stages, seven specimens of normal-appearing adjacent mucosa, and three specimens of normal colonic mucosa. Colectomy specimens from five patients were assayed for N-myristoyltransferase activity. Subcellular distribution of N-myristoyltransferase activity was determined. Synthetic peptides of known myristoylated proteins--pp60src and cyclic adenosine monophosphate-dependent protein kinase--were used in kinetic analyses of N-myristoyltransferase in colonic cancer and normal-appearing colonic tissue. All P values are two-tailed. RESULTS: N-Myristoyltransferase activity was increased in rat colonic tumors compared with normal-appearing adjacent mucosa and normal mucosa (P = .0002). Elevation of N-myristoyltransferase activity was present in all tumors, including colonic polyps. Increased N-myristoyltransferase activity was also observed in human colonic tumors and was predominantly cytosolic. N-Myristoyltransferase of colonic cancer tissues had a similar Michaelis constant but an approximate twofold higher maximum velocity for both the pp60src- and cyclic adenosine monophosphate-dependent protein kinase-derived peptides compared with N-myristoyltransferase of normal-appearing tissue. CONCLUSIONS: This study demonstrates for the first time that N-myristoyltransferase activity is higher in colonic epithelial neoplasms than in normal-appearing colonic tissue and that an increase in N-myristoyltransferase activity appears at an early stage in colonic carcinogenesis.

Acyltransferases↗
PubMed1998

A fish oil-derived concentrate enriched in eicosapentaenoic and docosahexaenoic acid as ethyl esters inhibits the formation and growth of aberrant crypt foci in rat colon.

It was examined whether the fish oil derived n-3 fatty acid concentrate K85 (51.0% of eicosapentaenoic acid, 35.3% of docosahexaenoic acid and 7.7% of other n-3 fatty acids, all as ethyl esters) could inhibit the initial formation of aberrant crypt foci and the later growth of pre-existing aberrant crypt foci in the colon of male F344 rats treated with the carcinogens dimethylhydrazine or azoxymethane, the proximate metabolite of dimethylhydrazine. Given intragastrically 5 times a week, K85 caused a dose-dependent reduction of the initial (week 0-6) formation of aberrant crypt foci induced by azoxymethane (2 x 15 mg/kg body weight/injection the first two weeks). The number of aberrant crypt foci was reduced by 36% (P < 0.001) with 3.0 g K85/kg body weight/dose, the largest dose tested. The reduction was most pronounced (46%, P = 0.009) among the fastest growing aberrant crypt foci (foci with 3 or more aberrant crypts). When given in a later phase of the carcinogenesis (week 17-23) a similar intragastric treatment with K85 caused a dose-dependent reduction of the growth of pre-existing aberrant crypt foci induced by dimethylhydrazine (3 x 20 mg/kg body weight/injection the first week). The crypt multiplicity (aberrant crypt/focus) was reduced by 22% (P = 0.016) with 2.24 g K85/kg body weight/dose, the largest dose tested. This was sufficient to completely block the growth of the pre-existing aberrant crypt foci in the treatment period. The arrest of crypt multiplication was further documented by the 63% reduction (P = 0.03) of the large aberrant crypt foci (foci with 9 or more aberrant crypts). The total number of aberrant crypt foci was not affected.

Animals↗
PubMed1984

Human colon cells: culture and in vitro transformation.

Normal human colon mucosal epithelial cells were cultured in vitro and treated with the oncogenic simian DNA virus (SV40) and the chemical carcinogen azoxymethane. Both SV40 and azoxymethane altered a number of phenotypic characteristics of the normal human colon cells, including their morphology, culture longevity, growth in soft agar, substrate adherence, and peanut agglutinin binding. The SV40 transformants synthesized intranuclear T antigen. These data indicate that normal human colon mucosal cells were transformed toward the malignant phenotype.

Antigens, Viral, Tumor↗
PubMed1985

Effect of warfarin on cell kinetics, epithelial morphology and tumour incidence in induced colorectal cancer in the rat.

The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as determined by stathmokinetic techniques), and preneoplastic morphological changes was studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or high dose, had no effect on crypt cell production rate (CCPR) at any time interval whereas tumour incidence in both low dose warfarin and high dose warfarin groups was significantly reduced. Morphological changes were observed using scanning electron microscopy, which by conventional histology were shown to be adenoma precursors. In the control group the number of microadenomas increased with time after starting azoxymethane. In warfarin treated animals, the number of microadenomas also increased with time, but the actual incidence was reduced when compared with controls. These results suggest that the effects of warfarin on tumour development is unrelated to its anticoagulant effect, because increased dose did not result in greater tumour reduction. Furthermore, there was no overall change in CCPR when warfarin was administered. Warfarin may exert a specific effect, by preventing neoplastic change in cells which have undergone morphologically undetectable changes associated with early carcinogenesis.

Adenoma↗