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PubMed2003

Chemoprevention for colorectal tumorigenesis associated with chronic colitis in mice via apoptosis.

The mechanism of the suppressive effect of nonsteroidal anti-inflammatory drugs in azoxymethan and dextran sulfate sodium-induced colonic aberrant crypt foci/tumors associated with chronic colitis in mice was studied. With administration of sulindac, a cyclooxygenase-1 and -2 inhibitor, the mean number of colonic aberrant crypt foci/tumors was significantly smaller than that of controls. There was no significant difference in prostaglandin E2 content in the colonic mucosa between the groups. Furthermore, nimesulid, a cyclooxygenase-2 selective inhibitor, also suppressed colonic aberrant crypt foci/tumors as well as sulindac. Administration of nimesulid caused apoptosis indices to be significantly higher along with cyclooxygenase-2 expression being significantly lower than in controls. Apoptosis indices of 400 ppm group of nimesulid were significantly higher than that of 200 ppm group. Nonsteroidal anti-inflammatory drugs distinctly suppress the occurrence of aberrant crypt foci/tumors in this murine colitis-associated neoplasia model. Induction of apoptosis is a more important factor for chemoprevention than this reduction of prostaglandin E2.

Animals↗
PubMed2003

Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system.

The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.

Animals↗
PubMed2003

Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer.

K-ras mutations occur frequently in colon cancer and contribute to autonomous growth. In the azoxymethane (AOM) model of colon cancer, in addition to K-ras mutations, we have shown that wild-type (WT) Ras can be activated by upstream pathways, including, e.g., signaling by ErbB receptors. Tumors with mutant or activated WT Ras had increased cyclooxygenase-2 (Cox-2) expression. We have also shown that ursodeoxycholic acid (UDCA) prevented AOM-induced colon cancer and suppressed Cox-2 induction. In this study, we examined the role of Ras in Cox-2 inhibition by UDCA. Rats were fed AIN-76A chow alone, or supplemented with 0.4% UDCA, and received 20 mg/kg AOM i.p. weekly x 2 weeks. At 40 weeks, rats were sacrificed, and tumors were harvested. K-ras mutations were assessed by primer-mediated RFLP, allele-specific oligonucleotide hybridization, and direct DNA sequencing. Ras was immunoprecipitated and defined as activated if [Ras - GTP/(Ras - GTP + Ras - GDP)] was >3 SD above normal colonocytes. Cox-2 mRNA was determined by reverse transcription-PCR, and protein expression was assessed by Western blotting and immunostaining. In the AOM alone group, Ras was activated by mutations in 8 of 30 (27%) tumors, and WT Ras was activated in 7 of 30 (23%) tumors. UDCA significantly suppressed the incidence of tumors with mutant Ras (1 of 31, 3.2%; P < 0.05) and totally abolished the development of tumors with activated WT Ras (0 of 10; P < 0.05). In the AOM alone group, Cox-2 was up-regulated >50-fold in tumors with normal Ras activity and further enhanced in tumors with mutant or signaling-activated Ras. UDCA significantly inhibited Cox-2 protein and mRNA levels in tumors with normal Ras activity. In summary, we have shown for the first time that UDCA suppressed the development of tumors with Ras mutations and blocked activation of WT Ras. Furthermore, UDCA inhibited Cox-2 induction by Ras-dependent and -independent mechanisms.

Animals↗
PubMed2003

Energy restriction reduces the number of advanced aberrant crypt foci and attenuates the expression of colonic transforming growth factor beta and cyclooxygenase isoforms in Zucker obese (fa/fa) rats.

Several epidemiological studies have supported the concept that high energy intake, obesity, and/or hyperinsulinemia are risk factors for colon cancer. Previously, it was shown that Zucker obese rats are more sensitive to chemically induced colon cancer than their lean counterparts. The present study investigated whether moderate (20-25%) dietary energy restriction (ER) would attenuate colon carcinogenesis in the Zucker obese rat model. Six-week-old Zucker obese (fa/fa) rats and lean (Fa/Fa) rats received s.c. injections of azoxymethane at a dose of 10 mg/kg body weight once weekly for 2 weeks. A week later, obese rats (n = 16) were assigned to an ER diet (Ob-ER group), based on a low-fat AIN-93G semisynthetic diet. The remaining obese and lean rats (n = 16 rats/group) were fed the low-fat diet ad libitum (Ob group and Ln group, respectively). All rats were euthanized after 8 weeks, and their colons were assessed for aberrant crypt foci (ACF; n = 8/group) or for the expression of transforming growth factor (TGF)-beta and cyclooxygenase (COX) isoforms at the protein and mRNA transcript levels (n = 8/group). Ob rats had a higher number of advanced ACF (crypt multiplicity >or=7) than Ln rats. Dietary ER significantly reduced the appearance of advanced ACF in Ob-ER rats without significantly affecting the blood insulin level or body weights. TGF-beta and COX isoforms were differentially expressed in the colonic mucosae of Ob and Ln rats. Dietary ER significantly reduced TGF-beta1/beta2 and COX-1/2 protein expression in obese rats. This study is the first to demonstrate that moderate ER attenuated TGF-beta and COX protein expression and the carcinogenic process in Zucker obese rats. These findings provide insights leading to the proposal that the mechanism(s) underlying the early events of colon carcinogenesis in Zucker obese rats may extend beyond the role of excessive body weight and hyperinsulinemia per se.

Animals↗
PubMedDate not supplied

Chemopreventive effect of a probiotic preparation on the development of preneoplastic and neoplastic colonic lesions: an experimental study.

BACKGROUND/AIMS: A number of studies have suggested a key role played by certain resident gut bacteria in the development of large bowel cancer. The aim of the present study was to test the effect of a novel symbiotic preparation, which has been recently shown to beneficially modify gut ecosystem and systemic immunity, on either preneoplastic and neoplastic changes in a colon carcinogenesis model. METHODOLOGY: Sprague-Dawley rats were fed a standard diet for 1 week and then were randomly assigned to three groups. The control diet was given to groups A and B, whereas in group C, the same diet plus 2 mL of a probiotic mixture was given throughout the experiment. Thirty rats (groups B, C) each received a weekly subcutaneous injection of azoxymethane at a dose of 15 mg/kg of body weight for 10 weeks. Group A served as a control group and received a subcutaneous injection of saline for 10 weeks. Forty-five rats were sacrificed at 3-week observation and 60 rats at 20-week observation for assessing metaphase index together with aberrant crypt foci and intestinal immune system markers from one hand and tumor occurrence from the other, respectively. RESULTS: Group A showed a significantly increased metaphase index either in aberrant crypt foci or in "normal appearing" crypts when compared to group A (p < 0.01). Group B rats caused a significant decrease at both sites (p < 0.05). The numbers of lymphocytes derived from the mesenteric lymph nodes in group B rats were significantly decreased (p < 0.01) as compared to either control and to group C. The percentage of CD8 lymphocytes in group C was significantly higher than that in group B. Group C showed a significantly reduced ratio of aberrant crypt foci/colon and of aberrant crypt per colon and per each single focus (p < 0.05). A total of 18 (90%) group B and 10 (50%) group C rats had colon tumors, this difference was significant. The mean number of colon tumors per rat was 2.2 and 1.0 in group B and C, respectively. CONCLUSIONS: Effective probiotics treatment, through mechanisms still to be fully elucidated (decreased fecal pH, specific reduction of carcinogenetic bacterial enzymes, modulation of gut-associated and systemic immune system etc.) has the potential to exert significant antimutagenic properties against colon cancer.

Animals↗
PubMedDate not supplied

Efficacy of garbanzo and soybean flour in suppression of aberrant crypt foci in the colons of CF-1 mice.

BACKGROUND: Epidemiological studies have reported a low incidence of colon cancer in countries with high legume consumption. Moreover, experimental studies have found that legumes, such as soybeans and pinto beans, have anticancer properties. While garbanzo beans are a rich source of various phytochemicals, they have not been well studied. In the present study, the azoxymethane (AOM)-induced aberrant crypt foci (ACF) in CF-1 mice was utilized as a model to assess and compare the effects of garbanzo flour to that of soy flour. MATERIALS AND METHODS: Twenty, 5-week-old CF-1 mice were divided into four groups of 5 animals each: 10% garbanzo, 10% soy, 10% mixed (soy and garbanzo flours), and control (rodent chow). Animals received subcutaneous injections of AOM (10-mg/kg B. W.) once a week for two weeks to induce ACF. At week ten, the animals were sacrificed and the colons were scored. RESULTS: There was a 64% (p <0.001) suppression of ACF for animals fed the garbanzo flour, versus an inhibition of 58 and 55% (p<0.001) for the soy and mixed flour groups, respectively. DISCUSSION: These results demonstrate that garbanzo beans possess bioactive compounds capable of inhibiting the formation of pre-cancerous lesions in mice and suggest that, like soybeans, their consumption contributes to a reduction in colon cancer incidence.

Animals↗
PubMed2005

Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis.

Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1(+/-) and Folbp1(-/-)) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1(+/-)). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1(+/-) and Folbp1(-/-) mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1(+/+) mice. Colonic cell proliferation was increased in RFC1(+/-) mice relative to RFC1(+/+) mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1(+/+) mice, RFC1(+/-) mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1(+/-) mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1(+/+) mice. In contrast, Folbp1(+/-) mice developed 4-fold (P < 0.05) more lesions relative to Folbp1(+/+) mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.

Animals↗
PubMed2005

A high-fat diet enhances the inhibitory effect of dietary vitamin B6 on colon cell proliferation in mice.

Previously we reported that dietary supplemental vitamin B6 (B6) reduced colon tumorigenesis and cell proliferation in mice receiving azoxymethane (AOM) for 22 weeks. This study was conducted to examine the influence of short-term consumption (5 weeks) of diets containing graded levels of B6 and fat on colonic cell proliferation in mice with or without receiving AOM. In experiment 1, mice were fed the 10% corn oil diet containing 1, 7, 14, 35 or 70 mg pyridoxine HCl/kg, and received weekly injections of AOM for the initial 3 weeks. In experiment 2, mice were fed 5 or 20% corn oil diet containing 1, 7, 14 or 35 mg pyridoxine HCl/kg, and received weekly injections of AOM or saline for the initial 3 weeks. In experiment 1, supplemental B6 caused a dose-dependent reduction of colon aberrant crypt foci and cell proliferation (BrdU-labeling index) among the 1-14 mg pyridoxine HCl/kg. There was no influence of B6 on these parameters among 14-70 mg pyridoxine HCl/kg. Immunohistochemical analysis of apoptosis labeling by TUNEL method indicated no influence of dietary B6 on colon apoptosis. In experiment 2, supplemental B6 significantly reduced colon cell proliferation regardless of AOM injection. This inhibitory effect on cell proliferation was markedly enhanced by a high-fat diet, but slightly affected by AOM treatment. The results suggest that dietary supplemental B6 inhibits colon cell proliferation from the early stage of colon carcinogenesis, and a high-fat diet markedly enhances the inhibitory effect.

Animals↗
PubMedDate not supplied

Increased levels of PPARbeta/delta and cyclin D1 in flat dysplastic ACF and adenomas in Apc(Min/+) mice.

BACKGROUND: In Apc(Min/+) (Min; multiple intestinal neoplasia) mice two separate populations of aberrant crypt foci (ACF) develop in the colon after azoxymethane (AOM) exposure. ACF(Min), with a flat appearance, severe dysplasia and increased beta-catenin expression, are related to adenoma development, whereas classic ACF, with elevated structure, hyperplasia and normal beta-catenin level, are probably not. MATERIALS AND METHODS: The expressions of peroxisome proliferator-activated receptors (PPARs) beta/delta, cyclin D1 and beta-catenin in ACF, adenoma and normal tissue from AOM-treated Apc(Min/+) mice and a familial adenomatous polyposis (FAP) patient colon tumour were assessed by immunohistochemistry and immunoblotting. RESULTS: The flat ACF (ACF(Min)) displayed increased cytoplasmic levels of beta-catenin, and increased levels of cyclin D1 and PPARbeta/delta. In contrast, the expression in classic ACF resembled normal mucosa. Adenomas from Apc(Min/+) mice, as well as a FAP patient colon tumour, displayed increased nuclear and cytoplasmic levels of beta-catenin, and the same expression patterns of cyclin D1 and PPARbeta/delta as those found in flat ACF. CONCLUSION: In addition to activation of the Wnt signalling pathway in both flat ACF and in adenomas in Apc(Min/+) mice, the increased expression of PPARbeta/delta in these lesions could be a target for pro-inflammatory signals important for growth and reduced apoptosis.

Adenoma↗
PubMedDate not supplied

Reduced expression level of mgmt mRNA and beta-catenin gene mutation in rat colon tumors.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein and protects DNA from the biological effects of alkylating carcinogens. The purpose of this study was to investigate the association between the mRNA expression level of the Mgmt gene and mutation of the beta-catenin gene in rat colon tumors induced by azoxymethane (AOM) plus dextran sulfate sodium (DSS). MATERIALS AND METHODS: Eleven tumor samples from rat colon treated by AOM plus DSS were examined. Mutation of the beta-catenin gene was identified by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. The expression level of Mgmt mRNA was determined by reverse transcription-PCR (RT-PCR). RESULTS: Four out of five adeno-carcinoma samples bearing beta-catenin gene mutation (5 out of 11, 45%) displayed a decrease in expression levels of Mgmt mRNA (p<0.02). CONCLUSION: These results suggest that the reduced expression of Mgmt mRNA and beta-catenin gene mutation may contribute to the development of rat colon tumors.

Animals↗
PubMed1991

Effect of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis.

The effect of dietary menhaden oil containing omega-3 fatty acids and corn oil rich in omega-6 fatty acids fed during the initiation and/or postinitiation stages of colon carcinogenesis was investigated in male F344 rats. At 5 weeks of age, all animals were divided into seven groups (39 rats/group) and fed the semipurified diets containing 5% corn oil (LCO), 23.5% corn oil (HCO), or 18.5% menhaden oil plus 5% corn oil (HFO). At 7 weeks of age, all animals except the vehicle (normal saline)-treated groups were given two weekly s.c. injection of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight, once weekly. Three days after the second injection of AOM, groups of animals fed LCO, LCO, HCO, HCO, HCO, HFO, or HFO diets were transferred, respectively, to LCO, HCO, LCO, HCO, HFO, HCO, or HFO and continued on these diets until termination of the experiment. All animals were necropsied 42 weeks after carcinogen treatment. Body weights of animals fed various experimental diets during the initiation and postinitiation periods were comparable. As expected, the HCO diet fed during the postinitiation period significantly increased the AOM-induced incidence and multiplicity of colon adenocarcinomas, whereas the HCO diet fed during the initiation phase of carcinogenesis had no effect. Colon tumor incidence and multiplicity were significantly reduced in groups fed the HFO diet at either initiation and/or postinitiation phases of carcinogenesis as compared with those fed the HCO diet. Whereas the precise mechanisms producing the difference between the high menhaden oil (HFO) diet as compared with high corn oil (HCO) diet remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis, respectively.

Adenocarcinoma↗
PubMed1990

Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat.

We studied the effect of cooked food components on the promotion of microadenoma growth in the colons of mice and rats. CF1 mice and Fisher 344 rats were initiated with azoxymethane, with 152 mice receiving four weekly i.p. injections of 5 mg/kg, 59 rats receiving a single injection of 20 mg/kg, and 24 rats receiving 30 mg/kg. A week after the last injection, the animals were randomly assigned to one of eight diets with identical ingredients, but the three components, sucrose, casein, and beef tallow, either uncooked or cooked. Control animals were given diets with uncooked ingredients. Experimental animals were fed diets in which one, two, or three of the components were cooked in an oven at 180 degrees C until golden brown before they were added to the diet. After 100 days on the diets, the colons were fixed, stained with methylene blue, and scored for microadenomas. The mice and the rats fed cooked sucrose, or casein and beef tallow cooked together, had three to five times more large microadenomas than did the controls (P ranging from 0.02 to 0.0001). No significant increase was observed with the five other cooked diets. Two rats fed the casein and beef tallow cooked together had adenocarcinomas. Thus, a diet containing 20% of cooked sucrose, or 40% of casein and beef tallow cooked together, promotes the growth of colonic microadenomas in initiated mice and rats, and would appear to contain promoters for colon cancer.

Adenoma↗
PubMed1986

The effect of experimental carcinogenesis on intestinal diamine oxidase, a polyamine deaminating enzyme.

Intestinal mucosa hyperproliferation is an important risk factor of large bowel carcinoma development. Intestinal diamine oxidase (DAO) is suggested to be a proliferation terminating principle in the mature mucosa. Therefore, the influence of the carcinogen azoxymethane (AOM) on this enzyme was studied. The enzyme was measured with the 14C-putrescine assay. In vitro the enzyme was inhibited only by excessive high concentrations of AOM (89 mmol/liter). In vivo the enzymic activity was reduced in the duodenum but not in the colon during the first 48 hr after AOM application (15 mg/kg). Ten weekly injections of AOM reduced the DAO activity in the duodenum and colon significantly (alpha = 0.05). After the stop of the AOM application a significant (alpha = 0.05) increase of DAO activity over the control level was found which was interpreted as a defense reaction of the mucosa against the hyperproliferation that had occurred during the carcinogen treatment. Intestinal DAO is regarded as an antiproliferative principle protecting the integrity of the intestinal mucosa. An inhibition of this enzyme probably increases the risk of intestinal carcinoma promotion.

Amine Oxidase (Copper-Containing)↗
PubMed1988

Aberrant crypts: potential preneoplastic lesions in the murine colon.

Murine colons treated with the colon carcinogen azoxymethane (AOM) have been reported to contain aberrant crypts (AC), which are characterized by their larger size and wider pericryptal zones. The methodology used to visualize AC consists of staining the fixed, unsectioned colonic mucosa with methylene blue and transillumination of the luminal surface at a magnification of 40x. The objective of the present studies was to determine if AC demonstrate characteristics to support our hypothesis that they are putative preneoplastic lesions. Studies were designed to determine the time of occurrence of AC (Study I), the induction of AC in response to varying dosages of AOM ranging from 0.0 to 10.0 mg/kg body weight (Study II), and the effect of a high fat diet (20% fat by weight) on the number and size of AC (Study III). In all studies 4-6-week-old female CF1 mice were used. In addition C57BL/6J female mice were used in Study I. The major findings were as follows: (a) the time period required to form AC was approximately 2 weeks following a single AOM injection (5 mg/kg); (b) a dose-dependent increase in the induction of AC was noted in response to AOM from none in the control group to a plateau level of 2.90 +/- 0.38 foci at a dose of 5.0 mg/kg; (c) in comparison to the low fat group, the high fat group had a greater (P less than 0.05) mean number of foci of AC per 5 cm of colon (15.67 +/- 1.32 vs. 11.44 +/- 1.44) and a larger (P less than 0.05) mean size of foci of AC (0.0296 +/- 0.0012 mm vs. 0.0249 +/- 0.0012 mm) after 16 weeks on the respective diets; and (d) preliminary histological appearance of foci of AC revealed mild atypia to unequivocal dysplasia. The findings of the present study are consistent with the hypothesis that AC are putative preneoplastic lesions.

Animals↗
PubMed1988

Effect of dietary excess of inorganic selenium during initiation and postinitiation phases of colon carcinogenesis in F344 rats.

The effect of supplemental inorganic selenium given during the initiation or postinitiation phase of colon carcinogenesis induced by azoxymethane [(AOM)CAS:25843-45-2] was studied in male F344 rats. Weanling animals were raised on AIN-76A semipurified (control) diet. Starting at 4 wk of age, groups of animals intended for initiation study were fed the semipurified diets containing 0.5 and 2.5 ppm selenium in the form of sodium selenite, and those intended for postinitiation study were continued on the control diet. At 7 wk of age, all animals except the vehicle-treated controls were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 wk). One wk following AOM treatment, animals in the initiation study receiving the supplemental selenium were transferred to the control diet whereas those in the postinitiation study receiving the control diet were transferred to the diets containing 0.5 and 2.5 ppm selenium. These animals were continued on this regimen until the termination of the experiment at 34 wk post-AOM injection. Tissue and blood glutathione peroxidase activity was measured in vehicle-treated animals fed the control and selenium-supplemented diets. The results indicate that body weights were comparable among the various dietary groups. Feeding of diets containing 0.5 and 2.5 ppm selenium during the initiation phase had no effect on colon tumor incidence, but the multiplicity of adenomas was slightly inhibited in animals fed the 2.5 ppm selenium diet. The incidence and multiplicity of colon adenocarcinomas and the multiplicity of colon adenomas were inhibited in animals fed the 2.5-ppm selenium diet during the postinitiation phase of carcinogenesis. The incidence of small intestinal tumors was higher in animals fed the 2.5-ppm selenium diet during the initiation phase than in animals fed the control diet and 0.5-ppm selenium diet. Selenium-dependent glutathione peroxidase activity was increased in kidneys and small and large intestinal mucosae of animals fed the 2.5-ppm selenium diet compared to those fed the 0.5-ppm selenium and control diets.

Animals↗
PubMed1987

Proteolytic enzymes as new tumor markers in chemical carcinogenesis of intestinal tumors.

Because the role of proteolytic enzymes in carcinogenesis is not yet well understood, we studied two arylamidases cleaving Boc-(Ala)2-p-nitroanilide and Bz-Lys-p-nitroanilide in the sera of rats during azoxymethane (AOM)-induced development of bowel carcinomas. Both proteolytic activities exhibited similar patterns: During administration of the carcinogen they increased up to 2.1-fold (Boc-[Ala]2-Nan) and 1.7-fold (Bz-Lys-Nan) the activity of the control group (P less than 0.05). Subsequently they decreased, passing the normal range between weeks 16 and 20 after the first AOM treatment and then diminishing continuously with increasing manifestation of tumors. At week 24 when the last animals were sacrificed enzyme activities were only 36.5% and 43.7% of the controls (P less than 0.05). The early increase may be related to direct effects of the carcinogen. The decrease of serum activity in the further course, however, seems to be a typical event of invasive tumor growth, because a similar loss of activity was also observed in rats with benzopyrene sarcomas. We conclude that both arylamidases may become useful as nonspecific tumor markers.

Aminopeptidases↗
PubMed1987

Surgical prophylaxis against large bowel tumors in an animal model.

Subtotal removal of high-risk organs is of uncertain value as cancer prophylaxis. This study examined to what extent partial colectomy prevented carcinogen-induced large bowel tumors. Male Fischer 344 rats (N = 98) were given five weekly subcutaneous injections of azoxymethane 7 mg/kg, then treated as follows: group I (controls), the ileocecal junction was divided and reanastomosed without resection; group II, a proximal 1/3 colon resection was performed; and group III, a proximal 2/3 colon resection was performed. After 7 months the rats were sacrificed and colorectal tumors confirmed histologically. Sixty-nine animals survived for analysis. Tumor incidence and average number of tumors per rat were not significantly changed by resection. Surgical prophylaxis was compromised by a high frequency of multiple tumors and by a higher than expected frequency of tumors in the remaining bowel.

Animals↗
PubMed1987

Dose-related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal antiinflammatory drug, during different stages of rat colon tumor development.

The effect of four dose levels of piroxicam administered during different stages of colon tumor development was studied in male F344 rats to obtain a data base on the efficacy of piroxicam as an inhibitor of colon carcinogenesis. Piroxicam was added at levels of 25, 50, 75, and 150 ppm to the NIH-07 open-formula diet and fed to male F344 rats starting 1, 13, and 23 wk after the carcinogen administration. At 7 wk of age, while the animals were consuming the control diet, all animals except the vehicle-treated controls were given s.c. injection of azoxymethane (CAS:25843-45-2; 29.6 mg/kg body weight, once) to induce intestinal tumors. Forty wk after AOM injection, all animals were necropsied, and tumor incidences were compared among the various dietary groups. Colon tumor incidence (percentage of animals with tumors) was inhibited in a dose-dependent manner in rats fed the diets containing 25, 50, 75, and 150 ppm piroxicam starting 1 and 13 wk after carcinogen treatment. The colon tumor incidences in animals fed the diets containing 0, 25, 50, 75, and 150 ppm of piroxicam starting at 1 wk after carcinogen treatment were 89, 61, 58, 50, and 39%, respectively. When the diets containing 0, 25, 50, 75, and 150 ppm were fed 13 wk after carcinogen treatment, the colon tumor incidences were 89, 69, 69, 44, and 33%, respectively. Colon tumor multiplicity (tumors/animal; tumors/tumor-bearing animal) was also significantly inhibited in animals fed the diets containing 25 to 150 ppm piroxicam starting 1 and 13 wk after carcinogen administration. The number of colon tumors/animal was inhibited by about 80 to 84% in animals fed the 150 ppm piroxicam diet. When the diets containing different levels of piroxicam were fed 23 wk after carcinogen treatment, the colon tumor incidence was significantly inhibited in animals fed the 75 and 150 ppm piroxicam diets. The colon tumor incidences in animals fed the diets containing 0, 25, 50, 75, and 150 ppm were 89, 78, 67, 64, and 64%, respectively. The colon tumor multiplicity (colon tumors/animal) was slightly but significantly inhibited in animals fed the diets containing 25 to 150 ppm piroxicam. The results of this study demonstrate that increasing levels of piroxicam in the diet, when fed 1 or 13 wk after carcinogen insult, inhibit colon tumor incidence in a dose-dependent manner.

Animals↗