Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Azoxymethane”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed2000

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↗
PubMed1994

Oxygen free radical activity in experimental colonic carcinoma.

Oxygen free radical activity has been implicated in carcinogenesis through DNA lysis. This study measured chemiluminescence and superoxide dismutase (SOD) inhibition as an index of oxygen free radical activity in azoxymethane-induced colonic carcinoma. After 3 weeks of acclimatization, ten Fisher 344 rats were injected with azoxymethane (7 mg kg-1 week-1) over 10 weeks. All animals were killed at 37 weeks and colonic mucosa (5-25 mg wet weight) was sampled from sites of histologically confirmed gross tumour and sites 3-5 cm distant from tumour as well as from ten paired normal controls. The samples were processed in buffered luminol and chemiluminescence was measured in a luminometer. Each sample was then placed in a solution of SOD for 3 min before a second chemiluminescence estimation. Mean(s.e.m.) chemiluminescence from control mucosal samples decreased from 8.1(1.0) to 3.9(1.1) mV per 100 mg tissue (P < 0.05) after incubation in SOD, suggesting that oxygen free radical activity was being measured. There was an increase to 20.2(0.9) mV per 100 mg in azoxymethane-treated colon remote from tumour and to 53.9(2.1) mV per 100 mg at tumour sites; both were reduced significantly after incubation with SOD to 6.7(0.7) and 11.0(0.8) mV per 100 mg respectively (P < 0.001). Chemiluminescence was significantly increased in azoxymethane-induced colonic carcinoma, both remote from and maximally at the tumour site, suggesting a field change in carcinogenesis associated with oxygen free radical activity.

Animals↗
PubMedDate not supplied

Ingested asbestos and intestinal carcinogenesis in F344 rats.

The effect of oral exposure to amosite or chrysotile on azoxymethane-induced intestinal carcinogenesis was investigated in male F344 rats. In two separate experiments, F344 rats, 6 weeks of age, were given ten weekly subcutaneous injections of azoxymethane, and intragastric administration of amosite or chrysotile three times weekly during this period. In experiment 1, rats were sacrificed at 34 weeks. The incidence rates and mean number of intestinal tumors per rat were similar in all groups. However, a slightly higher incidence, not significant, of metastatic intestinal carcinomas was seen in rats exposed to asbestos. In the second experiment, rats were allowed to live out their life span. The incidence of intestinal tumors was similar in the rats receiving amosite with azoxymethane and azoxymethane alone. Thirty-two percent of the rats receiving amosite alone had colon tumors; these tumors are usually rare in F344 rats. It was concluded that the experimental evidence suggested but did not prove that oral asbestos exposure in F344 rats may have increased the incidence of intestinal tumors occurring naturally.

Animals↗
PubMed2001

Short term infusion of glycine-extended gastrin(17) stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa.

Evidence is accumulating that gastrin precursors may act as growth factors for the colonic mucosa in vivo and for colorectal carcinoma cell lines in vitro. The effect of short term administration of synthetic gastrins on the colonic mucosa in vivo, however, has not been reported. The aim of our study was to determine whether continuous systemic infusion of glycine-extended gastrin(17) stimulated proliferation and accelerated carcinogenesis in the colorectal mucosa. A significant increase in colonic mucosal proliferation as assessed by metaphase index was seen in the caecum (23%, p < 0.02) and distal colon (27%, p < 0.001), but not the rectum, after treatment of intact rats with glycine-extended gastrin(17) for 1 week using implanted miniosmotic pumps. Defunctioning of the rectum reduced both the proliferative index and crypt height of the rectal mucosa of untreated rats. Treatment of rectally defunctioned animals with glycine-extended gastrin(17) for either 1 or 4 weeks resulted in a significant increase in both the proliferative index (40% and 93%, respectively) and crypt height (11% and 19%, respectively) of the rectal mucosa. The total number of aberrant crypt foci in intact rats treated with the procarcinogen azoxymethane plus glycine-extended gastrin(17) was increased by 48% compared to the value in controls treated with azoxymethane only (p = 0.01). We conclude that short term administration of glycine-extended gastrin(17) to mature rats not only has a proliferative effect upon colonic mucosa, but also increases the number of aberrant crypt foci formed in the colorectal mucosa after treatment with azoxymethane. Glycine-extended gastrin(17) could thus potentially act as a promoter of carcinogenesis.

Animals↗
PubMed1998

Chemopreventive effect of aspirin on growth of aberrant crypt foci in rats.

Nonsteroidal anti-inflammatory drugs display a chemopreventive effect on polyps and cancer of the large bowel. This study evaluated the inhibitory effect of aspirin on the distribution and growth of aberrant crypt foci (ACF), the earliest putative preneoplastic and early neoplastic lesions in a rat model. For initiation of ACF, Sprague Dawley rats were injected with azoxymethane (30 mg/kg), a well-established rat carcinogen. After the second injection the rats were allocated to three groups, which received 0.2% or 0.6% aspirin or the solvent only (control group). After 6 weeks the animals were killed, and their colons removed, fixed in formalin, and screened for distribution and size of ACF, separately for middle and distal parts of the large intestine. The rats injected with azoxymethane showed a 100% incidence of ACF. Administration of 0.2% and 0.6% aspirin resulted in 55% and 54% reduction, respectively, in overall frequency of ACF. Aspirin significantly reduced the frequency of medium-sized (four to six crypts per focus) and large (three to six crypts per focus) but not the small (one to three crypts per focus) ACF. In the control group the ACF of the same multiplicity were larger than those in the aspirin-treated rats. No statistically significant difference in ACF-inhibiting effect was noted between 0.6% and 0.2% aspirin solution. Aspirin given at a concentration of either 0.2% of 0.6% thus has a chemopreventive effect on ACF, acting on postinitiation stage of azoxymethane-induced colonic carcinogenesis model in rats.

Animals↗
PubMed1976

Effect of diet high in beef fat on the composition of fecal bile acids during intestinal carcinogenesis in the rat.

Two groups of 20 male Sprague-Dawley rats each were given sc 8 mg azoxymethane/kg body weight and fed a normal diet or one high in beef fat. Control groups were not given azoxymethane. Fat-control animals did not excrete more total bile acids than did the normal-control group but did excrete more deoxycholic acid as the result of increased cholic acid degradation. Azoxymethane itself caused an increase in fecal bile acid concentratation but tended to reduce the level of cholic acid degradation. Fatty acid content in the feces increased in the animals on the fat diet but was not affected by azoxymethane. A fat-diet-dependent increase was apparent in total fecal neutral steroids and a carcinogen-dependent increase in cholesterol degradation. Dietary fat and bile steroids altered by gut microflora were important interrelated factors in the intestinal carcinogenic process of this animal model.

Animals↗
PubMed1997

Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets.

BACKGROUND: Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued. PURPOSE: Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets. METHODS: Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically. RESULTS: No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet. CONCLUSIONS: In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.

Adenocarcinoma↗
PubMed1996

Promotion of colorectal neoplasia in experimental murine ulcerative colitis.

BACKGROUND: The mechanisms underlying the frequent development of colorectal carcinomas in patients with ulcerative colitis are still unknown. AIMS: To evaluate whether mucosal necrosis and regeneration act as enhancing or promoting factors in colorectal tumorigenesis, development of multiple colorectal tumours was studied in a murine model of ulcerative colitis with azoxymethane pretreatment. METHODS: Periods of chronic ulcerative colitis in mice were induced by three repeated administrations of 3% dextran sulphate sodium subsequent to a single azoxymethane pretreatment, to give conditions similar to the clinically observed active and remission phases. RESULTS: In the chronic colitis group with carcinogen exposure, multiple mucosal tumours (10.5/mouse) developed in the colorectum. This occurred primarily on the left side of the large intestine or transverse colon, the sites of the most severe colitic injury. The observed lesions were high grade dysplasias and invasive adenocarcinomas. Increased cell proliferation was evidenced by high uptake of bromodeoxyuridine, and increased activities of thymidylate synthetase and thymidine kinase. No tumours were induced in the control groups with azoxymethane pretreatment or chronic colitis alone. CONCLUSIONS: Repeated mucosal erosion with necrosis and regeneration is critical for the development of colorectal tumours in this experimental colitis system.

Animals↗
PubMed2000

Effect of olive oil on early and late events of colon carcinogenesis in rats: modulation of arachidonic acid metabolism and local prostaglandin E(2) synthesis.

BACKGROUND: Animal model studies have shown that the colon tumour promoting effect of dietary fat depends not only on the amount but on its fatty acid composition. With respect to this, the effect of n9 fatty acids, present in olive oil, on colon carcinogenesis has been scarcely investigated. AIMS: To assess the effect of an n9 fat diet on precancer events, carcinoma development, and changes in mucosal fatty acid composition and prostaglandin (PG)E(2) formation in male Sprague-Dawley rats with azoxymethane induced colon cancer. METHODS: Rats were divided into three groups to receive isocaloric diets (5% of the energy as fat) rich in n9, n3, or n6 fat, and were administered azoxymethane subcutaneously once a week for 11 weeks at a dose rate of 7.4 mg/kg body weight. Vehicle treated groups received an equal volume of normal saline. Groups of animals were colectomised at weeks 12 and 19 after the first dose of azoxymethane or saline. Mucosal fatty acids were assessed at 12 and 19 weeks. Aberrant crypt foci and the in vivo intracolonic release of PGE(2) were assessed at week 12, and tumour formation at week 19. RESULTS: Rats on the n6 diet were found to have colonic aberrant crypt foci and adenocarcinomas more often than those consuming either the n9 or n3 diet. There were no differences between the rats on the n9 and n3 diets. On the other hand, administration of both n9 and n3 diets was associated with a decrease in mucosal arachidonate concentrations as compared with the n6 diet. Carcinogen treatment induced an appreciable increase in PGE(2) formation in rats fed the n6 diet, but not in those fed the n3 and n9 diets. CONCLUSIONS: Dietary olive oil prevented the development of aberrant crypt foci and colon carcinomas in rats, suggesting that olive oil may have chemopreventive activity against colon carcinogenesis. These effects may be partly due to modulation of arachidonic acid metabolism and local PGE(2) synthesis.

Adenocarcinoma↗
PubMed2004

COOH-terminal 26-amino acid residues of progastrin are sufficient for stimulation of mitosis in murine colonic epithelium in vivo.

Transgenic mice (hGAS) that overexpress human progastrin are more susceptible than wild-type mice (FVB/N) to the induction of colonic aberrant crypt foci (ACF) and adenomas by the chemical carcinogen azoxymethane. We have previously shown significantly increased levels of colonic mitosis in hGAS compared with FVB/N mice after gamma-radiation. To investigate whether the effects of progastrin observed in hGAS colon require the presence of other forms of circulating gastrin, we have crossed hGAS (hg(+/+)) with gastrin knockout (G(-/-)) mice to generate mice that express progastrin and no murine gastrin (G(-/-)hg(+/+)). After azoxymethane, G(-/-)hg(+/+) mice developed significantly more ACF than control G(-/-)hg(-/-) mice (which do not express any forms of gastrin). G(-/-)hg(+/+) mice also exhibited significantly increased colonic mitosis both before and after exposure to 8 Gray Gy gamma-radiation or 50 mg/kg azoxymethane compared with G(-/-)hg(-/-). Treatment of G(-/-)hg(-/-) mice with synthetic progastrin (residues 21-101 of human preprogastrin) or G17 extended at its COOH terminus corresponding to the COOH-terminal 26-amino-acid residues of human preprogastrin (residues 76-101, G17-CFP) resulted in continued colonic epithelial mitosis after gamma-radiation, whereas glycine-extended gastrin-17 and the COOH-terminal tryptic fragment of progastrin [human preprogastrin-(96-101)] had no effect. Immunoneutralization with an antibody against G17-CFP before gamma-radiation significantly decreased colonic mitosis in G(-/-)hg(+/+) mice to levels similar to G(-/-)hg(-/-). We conclude that progastrin does not require the presence of other forms of gastrin to exert proliferative effects on colonic epithelia and that the portion of the peptide responsible for these effects is contained within amino acid residues 76-101 of human preprogastrin.

Amino Acid Sequence↗
PubMed2006

Risk stratification of colon carcinogenesis through enhanced backscattering spectroscopy analysis of the uninvolved colonic mucosa.

INTRODUCTION: Our group has been interested in applying advances in biomedical optics to colorectal cancer risk stratification. Through a recent technological breakthrough, we have been able to harness information from enhanced backscattering spectroscopy, an optics phenomenon that allows quantitative, depth-selective analysis of the epithelial microscale/nanoscale architecture. In the present study, we investigated the ability of enhanced backscattering analysis of the preneoplastic mucosa to predict risk of colon carcinogenesis. METHODS: Enhanced backscattering analysis was done on intestinal mucosa at preneoplastic time points from two experimental models of colorectal cancer: the azoxymethane-treated rat and the multiple intestinal neoplasia (MIN) mouse. Data were analyzed using two previously validated spectral markers: spectral slope and principle components. We then did a pilot study on mucosal biopsies from 63 subjects undergoing screening colonoscopy. RESULTS: In the azoxymethane-treated rat, when compared with saline-treated controls, significant changes in the enhanced backscattering markers were observed as early as 2 weeks after azoxymethane treatment (before the development of aberrant crypt foci and adenomas). Enhanced backscattering markers continued to progress over time in a manner consonant with future neoplasia. These data were replicated in the preneoplastic MIN mouse mucosa. In humans, spectral slopes in the endoscopically normal cecum, midtransverse colon, and rectum were markedly reduced in patients harboring adenomas when compared with those who were neoplasia free. CONCLUSIONS: We show, for the first time, that enhanced backscattering analysis of an aliquot of uninvolved mucosa has the potential for predicting neoplastic risk throughout the colon in both experimental colorectal cancer models and humans.

Animals↗
PubMed2006

Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21(waf1/cip1) in colon cancer cells.

Extracts of Aesculus hippocastanum (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema, and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component beta-escin or aescin. Recent studies suggest that beta-escin may possess anti-inflammatory, anti-hyaluronidase, and anti-histamine properties. We have evaluated the chemopreventive efficacy of dietary beta-escin on azoxymethane-induced colonic aberrant crypt foci (ACF). In addition, we analyzed the cell growth inhibitory effects and the induction of apoptosis in HT-29 human colon cancer cell line. To evaluate the inhibitory properties of beta-escin on colonic ACF, 7-week-old male F344 rats were fed experimental diets containing 0%, 0.025%, or 0.05% beta-escin. After 1 week, the rats received s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 weeks) or an equal volume of normal saline (vehicle). Rats were continued on respective experimental diets and sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated histopathologically for ACF. Administration of dietary 0.025% and 0.05% beta-escin significantly suppressed total colonic ACF formation up to approximately 40% (P < 0.001) and approximately 50% (P < 0.0001), respectively, when compared with control diet group. Importantly, rats fed beta-escin showed dose-dependent inhibition (approximately 49% to 65%, P < 0.0001) of foci containing four or more aberrant crypts. To understand the growth inhibitory effects, HT-29 human colon carcinoma cell lines were treated with various concentrations of beta-escin and analyzed by flow cytometry for apoptosis and cell cycle progression. Beta-escin treatment in HT-29 cells induced growth arrest at the G1-S phase, which was associated with the induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), and this correlated with reduced phosphorylation of retinoblastoma protein. Results also indicate that beta-escin inhibited growth of colon cancer cells with either wild-type or mutant p53. This novel feature of beta-escin, a triterpene saponin, may be a useful candidate agent for colon cancer chemoprevention and treatment.

Aesculus↗
PubMedDate not supplied

The more an ulcerative colitis is repeated, the more the risk of colorectal carcinogenesis is increased in mice.

The incidence of colorectal carcinogenesis is increased in patients with ulcerative colitis. We investigated the effects of repetitive diarrhea on colorectal carcinogenesis in mice singly pretreated by a low-dose of chemical carcinogen. Mucosal changes were investigated in mice pretreated with a single intraperitoneal injection of 8.0 mg/kg body weight of azoxymethane prior to a repetitive oral administration of 3% dextran sulphate sodium to induce chronic diarrhea. Repetitive treatment with dextran sulphate sodium induced a cycle of chronic diarrhea-remission in the colorectum. Five submucosal-invasive adenocarcinomas and 65 high-grade dysplasias were found in 15 mice that underwent azoxymethane-pretreatment with 3 cycles of 3% dextran sulphate sodium-exposure, i.e. colorectal carcinogenesis was observed mainly in the left side of the large intestine within 11 weeks after the initial treatment with carcinogen. Consequently, thymidine kinase was expressed and activated, and an increase in bromodeoxyuridine-immuno-reactive (S-phase) cells was observed in the regenerating mucosa and the colorectum with tumorous lesions. Colorectal carcinogenesis developed with the increasing duration of diarrhea induced by 3% dextran sulphate sodium in mice pretreated by a single injection of a small dosage of azoxymethane during the comparatively short period of this experimental colitis system.

Adenocarcinoma↗
PubMed1991

Evaluation of dietary dehydroepiandrosterone for chemoprotection against tumorigenesis in premalignant colonic epithelium of male F344 rats.

Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA), an adrenal cortical steroid, has chemoprotective properties. Rat colonic epithelium which had been induced to a premalignant state by the colonic carcinogen azoxymethane was used as a model for patients at high risk of colorectal carcinoma, and the efficacy of dietary DHEA for chemoprotection against tumorigenesis was evaluated. Ten-week-old male F344 rats (n = 100) were given 10 weekly s.c. injections of azoxymethane at a dose of 10 mg/kg/week. One day after the final dose of carcinogen, DHEA was added to the diet of 50 rats (0.5% DHEA chow), and the other rats were used as pair-fed controls. DHEA-fed rats lost body weight throughout the 17-week study, in contrast to their pair-fed controls. Serum DHEA in DHEA-fed rats at the end of the study was 6 times that of controls (120 +/- 30 versus 18 +/- 14 pmol/ml), and serum DHEA sulfate was 23 times that of controls (1311 +/- 13 versus 55 +/- 13 pmol/ml). Addition of DHEA to the diet produced no significant chemoprotection in our model. Tumor-related mortality was somewhat increased in DHEA-fed rats (20% versus 6% in week 16 of DHEA feeding, P not significant). The cumulative prevalence of left colonic tumors, identified by weekly colonoscopic examinations, was somewhat lower in DHEA-fed rats than in controls during weeks 10 through 13 (17% versus 33% in week 12, P not significant), but in week 14 the prevalence in DHEA-fed rats became similar to that in controls (39% versus 41%). Growth curves of autochthonous left colonic tumors, as assessed for 8 weeks by computerized image analysis of colonoscopic photographs, were similar for DHEA-fed and control rats. Prevalence, mean frequency, multiplicity, and diameter of colonic tumors at necropsy of colonoscopically negative rats in week 17 were somewhat lower in the DHEA-fed rats (e.g., prevalence of 47% versus 67%), but the differences from controls were not significant. Parameters of colonic epithelial proliferation after tritiated thymidine incorporation in DHEA-fed rats were similar to those in control rats (labeling index of 8.3 +/- 0.7% versus 8.4 +/- 0.6% in week 17), despite higher serum DHEA and DHEA sulfate levels. Our findings indicate that DHEA did not have significant postinduction chemoprotective activity against azoxymethane-induced colonic tumorigenesis in this model utilizing pair-fed controls. Further preclinical studies appear to be needed before dietary DHEA can be recommended for chemoprotection trials in patients with premalignant colorectal epithelium.

1,2-Dimethylhydrazine↗
PubMed1995

Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent.

Epidemiological and laboratory animal model studies have suggested that nonsteroidal anti-inflammatory drugs reduce the risk of development of colon cancer. The present study was designed to investigate the chemopreventive action of 160 and 320 ppm (equivalent to 40 and 80% maximum tolerated doses) sulindac, a nonsteroidal anti-inflammatory drug, fed during initiation and postinitiation stages and 320 ppm sulindac fed during promotion/progression stages of azoxymethane-induced colon carcinogenesis in male F344 rats. Also investigated was the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phosphatidylinositol-specific phospholipase C, lipoxygenase, and cyclooxygenase activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 160 and 320 ppm of sulindac. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. Animals intended for tumor promotion/progression study were administered 320 ppm of sulindac in diet starting at 14 weeks after a second azoxymethane treatment. All animals continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phosphatidylinositol-specific phospholipase C, prostaglandin E2, cyclooxygenase, and lipoxygenase activities. The levels of sulindac and its metabolites in stomach, cecal, and fecal contents and in serum were analyzed. The results indicate that dietary sulindac at 160 and 320 ppm levels inhibited the incidence of invasive and noninvasive adenocarcinomas of the colon (P < 0.01-0.001) as well as their multiplicity (P < 0.01-0.0001) in a dose-dependent manner. Also, feeding sulindac during promotion/progression stages significantly suppressed the incidence (P < 0.0001) and multiplicity (P < 0.0001) of colonic adenocarcinomas. Dietary sulindac also suppressed the colon tumor volume by > 52-62% compared to the control diet. Dietary sulindac significantly decreased the activities of phosphatidylinositol-specific phospholipase C (32-51%) and levels of prostaglandin E2 (> 40%) in the colonic mucosa and tumors, but it had no significant (P > 0.05) effect on phospholipase A2 activity. The formation of cyclooxygenase metabolites, particularly prostaglandin E2, prostaglandin F2 alpha, prostaglandin D2, 6-ketoprostaglandin F1 alpha, and thromboxane B2, and lipoxygenase metabolites such as 8(S)- and 12(S)-hydroxyeicosatetraenoic acids were significantly reduced in colonic mucosa and tumors of animals fed 320 ppm sulindac.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1991

Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, alpha-difluoromethylornithine, 16 alpha-fluoro-5-androsten-17-one, and ellagic acid individually and in combination.

The chemopreventive action of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, D,L-alpha-difluoromethylornithine (DMFO), 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354), and ellagic acid (EA) administered in diet individually and in combination before and during initiation and postinitiation phases of azoxymethane-induced neoplasia of the intestine was studied in male F344 rats. The MTD levels of piroxicam, DFMO, DHEA analogue, and EA were determined in male F344 rats and found to be 500, 5,000, 500, and 10,000 ppm, respectively, in modified AIN-76A diet. When these agents were fed in combination, the MTD levels were: piroxicam plus DFMO, 250 and 2500 ppm; piroxicam plus DHEA analogue, 250 and 250 ppm; piroxicam plus EA, 250 and 5000 ppm; piroxicam plus DFMO plus DHEA analogue, 250, 2500, and 250 ppm; and piroxicam plus DFMO plus EA, 250, 2500, and 5000 ppm. From these MTD values, 40 and 80% MTD levels were calculated and tested for their efficacy. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing 40 and 80% MTD levels of piroxicam, DFMO, DHEA analogue, and EA individually and in combination. At 7 weeks of age, all animals except the vehicle-treated groups were administrated s.c. injections of azoxymethane (15 mg/kg body weight/week for 2 weeks). Animals intended for vehicle treatment received s.c. injections of an equal volume of normal saline. Fifty-two weeks after azoxymethane and saline treatment all the animals were necropsied, and colon and small intestinal tumor incidence (percentage of animals with tumors) and multiplicity (tumors/animal) were compared among various dietary groups. The results indicate that 40 and 80% MTD levels of dietary piroxicam and DFMO significantly (P less than 0.001) inhibited colon and small intestinal tumor incidence and multiplicity. DHEA analogue at 40% MTD level significantly decreased the small intestinal and colon tumor incidences (P less than 0.05), whereas 80% MTD of DHEA analogue inhibited only small intestinal tumor incidence. EA at 40 and 80% MTDs had no significant effect on colon tumor incidence (P greater than 0.05), but 80% MTD of EA showed a significant inhibitory effect on the incidence of small intestinal adenocarcinomas (P less than 0.01). In the combination study, 40 and 80% MTD levels of piroxicam plus DFMO significantly (P less than 0.001) inhibited colon adenocarcinoma incidence (8.3%) and multiplicity (0.08 +/- 0.04) (SE) when compared to colon adenocarcinoma incidence (72.2%) and multiplicity (1.14 +/- 0.18) in control diet-fed animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Chemoprevention of colon carcinogenesis by concurrent administration of piroxicam, a nonsteroidal antiinflammatory drug with D,L-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor, in diet.

The effect of three levels of piroxicam and three levels of D,L-alpha-difluoromethylornithine (DFMO) fed individually and in combination during the postinitiation phase of carcinogenesis was studied in male F344 rats to generate a data base on the efficacy and synergistic and additive effects of these compounds as inhibitors of colon carcinogenesis. The maximum tolerated dose of DFMO was determined in male F344 rats and found to be 5000 ppm in the AIN-76A diet. Piroxicam at levels of 25, 75, and 150 ppm and DFMO at concentrations of 400, 1000, and 4000 ppm (20, 50, and 80% maximum tolerated dose) in AIN-76 diet were tested individually and in combinations. At 7 weeks of age, while the rats were consuming the control diet (AIN-76A), all animals except the vehicle (saline)-treated controls were given a single s.c. injection of azoxymethane (CAS: 25843-45-2) at a dose level of 29.6 mg/kg body weight to induce intestinal tumors. One week after azoxymethane injection, animals were transferred to their respective experimental diets containing piroxicam and DFMO. Fifty-six weeks after azoxymethane injection, all animals were necropsied and colon and small intestinal tumor incidences and multiplicity were compared among the various dietary groups. Feeding of diets containing 75 and 150 ppm piroxicam or 1000 and 4000 ppm DFMO significantly inhibited the incidence (percentage of animals with tumors) of colon adenocarcinomas compared to that of control diet. The multiplicity (number of tumors/rat) of adenocarcinomas was significantly inhibited in animals fed the 25, 75, and 150 ppm piroxicam or 400, 1000, and 4000 ppm DFMO diets. Results analyzed by the linear regression method suggested a dose-dependent inhibition in colon adenocarcinoma incidence with increasing levels of piroxicam or DFMO. The incidence and multiplicity of colon adenocarcinomas were significantly inhibited in animals fed the diets containing combinations of 25, 75, and 150 ppm piroxicam and 400, 1000, and 4000 ppm DFMO. Piroxicam and DFMO administered together had a stronger inhibitory effect than did those given individually. Piroxicam and DFMO when administered individually had no significant inhibitory effect on colon adenoma incidence and multiplicity; in contrast, combinations of these compounds significantly inhibited colon adenomas. No consistent differences were found in the incidence and multiplicity of small intestinal tumors among the dietary groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1991

Experimental model of colon cancer: recurrences after surgery alone or associated with intraperitoneal 5-fluorouracil chemotherapy.

The liver is the most frequent site of metastases in colon cancer. No good animal model has been available to help improve the treatment of liver metastases or their prevention after resection of a primary colon cancer. The aim of this study was to develop a model of colon cancer induced by azoxymethane in the rat and to study the outcome after surgical resection alone or in association with intraperitoneal chemotherapy (5-fluorouracil (5-FU). Three hundred male Wistar rats received subcutaneous azoxymethane (10 mg/kg body weight/week) for 12 weeks. Eighty-three rats with isolated colon cancer underwent total colectomy; 40 of these rats with no metastases were randomized into two groups: surgery alone or surgery plus 5-FU (5 mg/kg body weight/day) for 5 days after surgery. Thirty rats were able to be evaluated. At autopsy, peritoneal carcinomatosis and liver metastases were more frequent in the control group than after adjuvant treatment with 5-FU (27.7 percent vs. 0, P less than 0.05; and 22.2 percent vs. 0, P less than 0.05, respectively). The rates of peritoneal and hepatic recurrence after resection of the primary cancer indicate that the model mimics the natural history of human colon cancer. In this model, 5-FU reduced the rate of peritoneal carcinomatosis and liver metastases but did not influence survival.

Adenocarcinoma↗