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PubMed1994

Ornithine decarboxylase inhibitor attenuates bombesin enhancement of intestinal carcinogenesis and metastasis induced by azoxymethane.

The effects of combined administration of bombesin (40 micrograms/kg body weight) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on the development of large and small intestinal tumors and the incidence of their metastasis to the peritoneum induced by azoxymethane (AOM, 7.4 mg/kg body weight), the ODC activity of the intestinal wall, and the labeling index of the intestinal mucosa and tumor were investigated in inbred Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, s.c. injections of bombesin every other day, and drinking water containing DAP (2.5 g/l) until the end of the experiment at week 40. Administration of bombesin significantly increased the incidence of intestinal tumors at week 40. It had no influence on the location, size, histological features or depth of involvement of intestinal adenocarcinomas, but significantly increased the incidence of their metastasis to the peritoneum. It also resulted in a significant increase in the intestinal ODC activity and labeling index. Administration of DAP with bombesin significantly reduced the enhancement of intestinal carcinogenesis by bombesin. Although the combined use of DAP with bombesin had little or no influence on the location, size, histological features, or depth of involvement of intestinal cancers, the incidence of their metastasis was significantly reduced. DAP significantly attenuated bombesin enhancement of the intestinal ODC activity and labeling index. These findings indicate that ODC inhibition attenuated the enhancement of intestinal carcinogenesis and metastasis to the peritoneum.

Adenocarcinoma↗
PubMed1995

Hypergastrinemia in rats with azoxymethane-induced colon cancers.

Gastrin has been suggested to be involved in the promotion and progression of colon cancer. Mice colon cancers and colon-carcinoma cell lines are stimulated to grow by gastrin, and gastrin receptors have been found in the majority of human colon-tumor specimens. High serum gastrin levels have been reported in patients with colon polyps and cancers, together with increased ornithine decarboxylase (ODC) activity. Since gastrin stimulates ornithine decarboxylase in colon cancer cells in vitro it has been suggested that increased synthesis of intracellular polyamines is one of the mechanisms activated by the hormone. In order to confirm the presence of hypergastrinemia in colon cancer and to investigate the relationship between plasma gastrin and tumor growth, we used an animal model of colon carcinogenesis that minimizes the possible bias of human studies, related to varying diet, age and environmental factors. We evaluated blood gastrin levels in 35 rats with colon cancer induced by the carcinogen azoxymethane (AOM), and we correlated gastrinemia with tumor proliferation, assessed by thymidine-labeling index (TLI) and ODC activity; 6 animals constituted the control group. Gastrin levels in rats with AOM-induced tumors were significantly higher than in controls. Significantly higher TLI and ODC activity were found in the tumors of hypergastrinemic rats than in neoplasms of animals with normal gastrin levels. Our data provide additional evidence of a role for gastrin as trophic hormone for colon neoplastic cells.

Animals↗
PubMed1995

Chemoprevention by galanin against colon carcinogenesis induced by azoxymethane in Wistar rats.

The effects of the neuropeptide galanin on the development of colon tumors induced by azoxymethane (AOM) and on the labeling index of colon epithelial cells were investigated in Wistar rats. Treatment with galanin significantly decreased the incidence of colon tumors at week 45. Galanin did not influence the histological appearance of the colon tumors, but it slightly increased the frequency of sub-mucosal adenocarcinomas. Furthermore, it significantly decreased the labeling index of colon mucosa during and after AOM treatment. These findings indicate that galanin inhibited the development of colon tumors and that this effect may be related to its suppression of colon-epithelial-cell proliferation.

Animals↗
PubMed1995

Suppression by amiloride of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane.

The effects of concomitant administration of bombesin and of the diuretic drug amiloride on the development of large and small intestinal tumors induced by azoxymethane (AOM), the incidence of their metastasis to the peritoneum and the labeling index of intestinal adenocarcinomas were investigated in inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM for 10 weeks and s.c. injections of bombesin and/or a higher or lower dose of amiloride hydrochloride (amiloride) every other day until the end of the experiment in week 45. Administration of bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal adenocarcinomas. Although administration of both doses of amiloride with bombesin had little or no influence on the enhancement of intestinal tumorigenesis by bombesin, the location, histological type, depth of involvement or labeling index of intestinal adenocarcinomas, a higher dose of amiloride significantly reduced the incidence of cancer metastasis to the peritoneum. Our findings indicate that amiloride possesses an anti-metastatic activity.

Adenocarcinoma↗
PubMed2001

Aberrant transforming growth factor-beta signaling in azoxymethane-induced mouse colon tumors.

Alterations in the transforming growth factor-beta (TGF-beta) pathway are implicated in the pathogenesis of colorectal cancer. We hypothesize that alterations in the TGF-beta pathway contribute to differential sensitivity of mice to the colon carcinogen azoxymethane (AOM). A/J (sensitive) and AKR/J (resistant) mice were injected intraperitoneally with AOM (10 mg/kg of body weight once a week for 6 wk). Twenty-four weeks after AOM exposure, mutational analysis of TGF-beta type II receptor (TbetaR-II) from normal colons and from tumors showed no AOM-induced alterations. A significant decrease (1.5-fold, P < 0.05) in TbetaR-II mRNA levels, however, was found in A/J tumors with the RNase protection assay. Immunofluorescence of TbetaR-II showed marked loss of staining in A/J tumors. The RNase protection assay and sequence analysis of the downstream signaling molecule Smad3 revealed no carcinogen-induced alterations in either strain. To gain further insight into the functionality of the pathway, expression of TGF-beta, TGF-beta type I receptor (TbetaR-I), and several downstream targets of TGF-beta signaling, including Smad7, c-myc, and p15, was examined. Although no alterations in TGF-beta, TbetaR-I, or Smad7 were found in tumors, a significant increase in c-myc expression (2.5-fold, P < 0.05 ) and a significant decrease in p15 expression (4.5-fold, P < 0.05 ) were noted. Concomitant repression of TbetaR-II and overexpression of c-myc may render epithelial cells insensitive to TGF-beta-mediated growth arrest, a possibility that also is suggested by this model. The significant decrease in p15 expression in tumors provides additional evidence that TGF-beta signaling may be markedly attenuated during colon tumorigenesis.

Adenoma↗
PubMed1991

Mutational specificities of environmental carcinogens in the lacl gene of Escherichia coli H. V: DNA sequence analysis of mutations in bacteria recovered from the liver of Swiss mice exposed to 1,2-dimethylhydrazine, azoxymethane, and methylazoxymethanolacetate.

The host-mediated assay (HMA) was used to determine the spectra of mutations induced in the lacl gene of Escherichia coli cells recovered from the livers of Swiss mice exposed to the carcinogens 1,2-dimethylhydrazine (SDMH), azoxymethane (AOM), and methylazoxymethanolacetate (MAMA). These spectra were further compared with changes induced by dimethylnitrosamine (DMNA) in the HMA methodology. A total of 177 independent lacl mutations arising in the HMA following exposure to SDMH, AOM, and MAMA were analyzed. Single-base substitutions accounted for 97% of all mutations analyzed. The vast majority of the single-base substitutions consisted of G:C----A:T transitions (94% of all mutations). The remaining mutations consisted of A:T----G:C transitions (3% of all mutations) while non-base substitutions accounted for only 3% of the total mutagenesis. The latter mutations consisted of one frameshift mutation and four lacO deletions. The distribution of G:C----A:T transitions induced by the three chemicals in the first 200 bp of the lacl gene was not random, but rather clustered at sites where a target guanine was flanked at the 5' site by a purine residue.

1,2-Dimethylhydrazine↗
PubMed2001

Inhibition of azoxymethane-induced aberrant crypt foci formation in rat colorectum by whole leaf Aloe arborescens Miller var. natalensis Berger.

We examined the modifying effect of whole-leaf Aloe arborescens Miller var. natalensis Berger (designated as 'ALOE') on azoxymethane (AOM)-induced aberrant crypt foci (ACF), putative preneoplastic lesions, in the rat colorectum. Male F344 rats (4 weeks old) were fed the basal diet, or experimental diets containing 1% or 5% ALOE for 5 weeks. One week later, all rats except those in the vehicle-treated groups were injected s.c. with AOM (15 mg/kg, once weekly for 3 weeks). At 9 weeks of age, all the rats were killed, and the colorectum and liver were evaluated for ACF and cytosolic quinone reductase (QR; a phase 2 enzyme), respectively. In rats given AOM and ALOE (1% or 5% in diet) the numbers of ACF/colorectum, aberrant crypts/colorectum, aberrant crypts/focus and large ACF/colorectum were significantly decreased compared with those of rats given AOM alone (all p < 0.01). No ACF were found in rats treated without AOM. In addition, ALOE significantly increased cytosolic QR activity in the liver (p < 0.01). These results indicated that ALOE inhibited the development of AOM-induced ACF in the rat colorectum, with increased QR activity in the liver, and therefore suggested that ALOE might have a chemopreventive effect against colon carcinogenesis at least in the initiation stage.

Aloe↗
PubMed1997

Effect of intestinal bacteria on formation of azoxymethane-induced aberrant crypt foci in the rat colon.

The effect of intestinal bacteria on formation of azoxymethane (AOM)-induced aberrant crypt foci (ACF) and DNA adducts in the rat colon was investigated. Male Sprague-Dawley rats were administered cultures of Lactobacillus acidophilus, Bifidobacterium adolescentis, Bacteroides fragilis, Escherichia coli and Clostridium perfringens for five weeks and given injections of AOM at 15 mg/kg body weight at the first and second weeks. The number of ACF five weeks after the start of the experiment was decreased in the rats treated with the cultures or culture supernatants of L. acidophilus and C. perfringens. The half-life of O6-methylguanine (O6-meG) in the L. acidophilus group was shorter than that in the GAM broth group. The half-life of 7-methylguanine did not differ among the groups. These results suggest that the metabolite(s) of L. acidophilus and C. perfringens inhibit(s) the ACF formation in rats treated with AOM and that the inhibitory effect of L. acidophilus is due to the enhanced removal of O6-meG from the colon mucosal DNA.

Animals↗
PubMed1999

Effects of beta-glucuronidase-deficient and lycopene-producing Escherichia coli strains on formation of azoxymethane-induced aberrant crypt foci in the rat colon.

We tried to inhibit the formation of azoxymethane-induced aberrant crypt foci (ACF) in the rat intestine by feeding a culture of a beta-glucuronidase-deficient Escherichia coli strain or a cell suspension of a lycopene-producing E. coli strain. Feeding of the former culture to F344 rats did not decrease fecal beta-glucuronidase activity or the number of ACF compared with the control beta-glucuronidase-proficient groups. However, a significant positive correlation between the fecal beta-glucuronidase activity and the ACF number was observed among groups treated with cultures of beta-glucuronidase-proficient and -deficient strains. In the group treated with lycopene-producing cells, the number of ACF was significantly lower than that in the control group. A vegetable juice containing a larger amount of lycopene than a cell suspension of the lycopene-producing E. coli also decreased the number of ACF to the same extent as a cell suspension of the lycopene-producing bacteria. These results suggest that feeding of the beta-glucuronidase-deficient E. coli is not very effective in preventing colon carcinogenesis, although activity of the fecal beta-glucuronidase is associated with AOM-induced ACF formation, and that lycopene-producing intestinal bacteria can effectively prevent colon carcinogenesis.

Animals↗
PubMed1998

Initial levels of azoxymethane-induced DNA methyl adducts are not predictive of tumor susceptibility in inbred mice.

Inbred mice vary in susceptibility to colon carcinogens such as 1,2-dimethylhydrazine (DMH). Differential susceptibility may depend, in part, on formation of promutagenic DNA methyl adducts within target colonic mucosa. The present study was undertaken to evaluate the extent of DNA adduct formation in susceptible (SWR) and resistant (AKR) mice acutely exposed to the colon carcinogen azoxymethane (AOM), a direct metabolite of DMH. In the first experiment, 8-week-old SWR and AKR mice were treated i.p. with 20 mg/kg AOM and sacrificed 6 h later. DNA was isolated from distal colon and liver, and O6-methylguanine (O6-MeGua) adduct levels were assessed by immunoslot blot (ISB) analysis, using a monospecific antibody raised against O6-methyldeoxyguanosine. HPLC-fluorescence detection was also used to quantitate 06-MeGua and 7-methylguanine (7-MeGua), and to generate standard curves. At 6 h, both O6-MeGua and 7-MeGua were significantly higher (2- to 3-fold, p < 0.05) in AKR colon, while an opposite pattern was found in liver. In Experiment 2, mice were injected with AOM (20 mg/kg) and euthanized 12 and 48 h later. At 12 h, O6-MeGua levels were higher in colons (1.4-fold) of SWR mice. Forty-eight hours after treatment, however, adduct levels in colon were markedly (5-fold) reduced in SWR but were unchanged from 12 h in AKR. To further compare activation of AOM in both strains, colon microsomes were incubated with AOM and calf thymus DNA. Comparable levels of O6-MeGua were detected by ISB, demonstrating equivalent metabolic capacity in both SWR and AKR mice. These studies suggest that differential susceptibility to AOM-induced colon carcinogenesis is not based on initial target tissue DNA alkylation and unlikely to depend on differential metabolic capacity.

Animals↗
PubMed1999

Microsatellite instability is infrequent in azoxymethane-induced rat intestinal tumors: An assessment by capillary electrophoresis.

A rat model of colon cancer in which tumors are induced by azoxymethane (AOM) is frequently used to study putative environmental agents that may modify the risk of human colon cancer development. In order to evaluate the usefulness of this model for human risk assessment, a comparison of the molecular changes associated with tumorigenesis in the rat model with those in human colon cancer is desirable. Microsatellite instability (MSI), an alteration in length of short repetitive DNA sequences associated with defective DNA mismatch repair, is an important molecular characteristic of many human colon tumors. Intestinal tumors were induced in male Fischer 344 rats injected with 15 mg/kg body wt AOM in four weekly doses. Thirteen intestinal tumors were examined for MSI at 10 different microsatellite loci, using a capillary electrophoresis (CE) method for accurate assessment of DNA length. This method was shown to have a resolution of 1 bp for a 140-bp PCR product and to be capable of detecting one mutant sequence within a background of 10 wild-type sequences. The CE method also readily distinguished a known MSI-positive human tumor sample from its matching control sample. Among the 13 rat intestinal tumors examined, only one had MSI, which was present at only a single locus. We conclude that, unlike sporadic human colon tumors in which 15-30% of tumors have MSI (usually at multiple loci), MSI is very rare in AOM-induced rat intestinal tumors.

Animals↗
PubMed1998

Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats.

The influence of bovine lactoferrin (bLf) on colon carcinogenesis was investigated in male F344 rats treated with azoxymethane (AOM). In experiment I, 2% and 0.2% bLf, and Bifidobacterium longum (B. longum) as a positive control at 3% were given in the diet for 4 weeks, along with two s.c. 15 mg/kg injections of AOM on days 1 and 8. The numbers of aberrant crypt foci (ACF) were decreased by both treatments. Similar results were obtained in experiment II of 13 weeks duration. In experiment III, animals were given three weekly injections of AOM and then received 2 or 0.2% bLf, 2% bLf-hydrolysate, or 0.1% bovine lactoferricin (bLfcin) for 36 weeks. No effects indicative of toxicity were noted, but significant reduction in both the incidence and number of adenocarcinomas of the large intestine was observed with almost all the treatments. Thus, the incidences of colon adenocarcinomas in the groups receiving 2 or 0.2% bLf, 2% bLf-hydrolysate, or 0.1% bLfcin were 15%, 25%, 26.3% and only 10%, respectively, in contrast to the 57.5% control value (p < 0.01). ACF values also exhibited reduced development. Investigation of beta-glucuronidase revealed decrease in the cecal contents of animals receiving bLf. In addition, demonstration of enhancement of NK activity by bLf indicated that its inhibitory effects could have been related to elevated immune cytotoxicity.

Animals↗
PubMed1977

Effect of propylthiouracil on intestinal tumor formation by azoxymethane in rats.

Treatment with propylthiouracil (PTU) resulted in a significant decrease in azoxymethane-induced intestinal tumors, total concentration of fecal bile acids as well as the fecal neutral steroids, cholesterol and coprostanol. Thus, a hypothyroid state induced by PTU treatment may affect intestinal carcinogenesis in this animal model by lowering the concentration of fecal bile acids and neutral steroids.

Adenocarcinoma↗
PubMed2003

Effect of diets fortified with tomatoes or onions with variable quercetin-glycoside content on azoxymethane-induced aberrant crypt foci in the colon of rats.

BACKGROUND: Onion and tomato are vegetables widely consumed by humans and epidemiological studies show an inverse association between vegetable consumption and colon cancer risk; however, the effect on colon cancer of diets containing high levels of vegetables like onion and tomato are not clear. AIMS OF THE STUDY: To investigate whether tomatoes and onions,with low or high quercetin-glycoside content, could reduce azoxymethane (AOM)-induced Aberrant Crypt Foci (ACF), preneoplastic lesions in the colon of rats. METHODS: Male Fisher 344 rats were fed the following diets: a) high fat (HF) diet (control diet); b) HF diet containing 20 % (w/w) tomatoes with a low quercetin-glycoside content (final concentration in the diet: 5 mg/kg of quercetin aglycone equivalents); c) HF diet containing 20% (w/w) high quercetin-glycoside tomatoes (100 mg/kg final concentration of quercetin aglycone equivalents); d) HF diet containing 20 % (w/w) low quercetin-glycoside onions (14 mg/kg of quercetin aglycone equivalents in the diet); e) HF diet containing 20 % (w/w) high quercetin-glycoside onions (360 mg/kg quercetin aglycone equivalents in the diet). After 2 wks of feeding, all rats were treated twice, 1 wk apart, with AOM (12 mg/kg, s. c.). The dietary treatments continued until sacrifice, 7 wks after the first injection with AOM. RESULTS: ACF induction did not vary in animals fed low or high quercetin-glycoside tomatoes relative to controls. On the contrary, rats fed 20% (w/w) onion-based diets, with low or high quercetin-glycoside content, showed an increase in number, multiplicity and "large" ACF compared to the control group (number of ACF/colon 145 +/- 15 (SE), 255 +/- 11 and 218 +/- 16 in controls, low and high-quercetin-glycoside groups, respectively; p < 0.01). Proliferative activity of the colon did not vary between animals fed control and high quercetin-glycoside tomato diet. The height of the crypts in normal mucosa of rats fed high quercetinglycoside onions was significantly increased compared to control rats (cells/emicrypt 38.4 +/- 1.2 (SE) and 41.3 +/- 0.6 in controls and high quercetin-glycoside onions group, p < 0.05). CONCLUSIONS: None of the diets supplemented with onion or tomato with variable quercetin-glycoside content demonstrated a potential chemopreventive effect on ACF-induction by AOM in rats.

Animals↗
PubMed2002

Effects of cyclooxygenase-2 inhibitor NS-398 on APC and c-myc expression in rat colon carcinogenesis induced by azoxymethane.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to protect against the development of colon cancer; however, the mechanism(s) by which NSAIDs exert their effects is still unclear. The aim of this study was to examine the effects of NSAIDs on the expression of the tumor suppressor APC gene and the c-myc oncogene in the colons of rats treated with a colon-specific carcinogen, azoxymethane (AOM). METHODS: Gene expression levels were estimated by a reverse transcription (RT)-competitive polymerase chain reaction (PCR) method. RESULTS: The group of rats simultaneously administered AOM and NS-398, a cyclooxygenase (COX)-2 inhibitor, showed a significant reduction in the number of preneoplastic lesions of colon cancer compared with that in the group of rats treated with AOM alone. Furthermore, the APC expression level in the group of rats treated with both AOM and NS-398 was significantly greater than that in the group of rats treated with AOM alone; this result for APC gene expression was reconfirmed by the immunohistochemical staining of APC protein. In addition, c-myc mRNA expression was clearly decreased in the group of rats treated with both AOM and NS-398 compared with the level in the group of rats treated with AOM alone. CONCLUSIONS: Our data thus indicate that NS-398 causes an increase in APC expression and a decrease in c-myc expression.

Animals↗
PubMedDate not supplied

Inhibition of carcinogenicities of 1,2-dimethylhydrazine and azoxymethane by pyrazole.

Inhibitory effects of pyrazole on the carcinogenicities of 2 large-bowel carcinogens, 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM), were examined, because our previous study revealed that pyrazole completely inhibited the induction of mutations by these carcinogens in the host-mediated mutation assay. ICR male mice were treated subcutaneously once a week for 20 weeks either with DMH or with AOM. Pyrazole was given orally to mice 2 h before treatment with the carcinogen. Pathological examinations were conducted 36 weeks after the first treatment. Treatment with DMH or AOM alone induced colorectal and/or anal tumorigenic lesions in 92% (23/25) mice of the DMH group and 100% (22/22) mice of the AOM group. By contrast, none of the animals in the combined treatment groups (carcinogen + pyrazole) developed those tumors. On the other hand, 50% (13/26) of mice treated with DMH alone and 78% (18/23) of mice treated with AOM alone developed vascular tumors. Pretreatment of mice with pyrazole reduced the percentage of mice bearing this type of tumor to about 30% of that in the carcinogen group with either carcinogen. These results clearly show that pyrazole has the ability to inhibit carcinogenicities of DMH and AOM, especially for the colorectum and anus, and indicate that the inhibition studies of mutation induction in vivo provide a useful tool for the screening for inhibitors of the carcinogenicities of DMH and AOM.

1,2-Dimethylhydrazine↗
PubMed1992

Dietary cholesterol enhances the induction and development of colonic preneoplastic lesions in C57BL/6J and BALB/cJ mice treated with azoxymethane.

The effect of dietary cholesterol on the induction and development of colonic precursor lesions was determined in two mouse strains, C57BL/6J and BALB/cJ, which differ in their metabolism of cholesterol. Mice were randomized into four groups and fed a cholesterol-free or a 1.25% cholesterol diet during and/or subsequent to four weekly injections of azoxymethane (5 mg/kg body wt.). Dietary cholesterol significantly increased the number of aberrant crypt foci (P less than 0.0001), enhanced cell proliferation (P less than 0.0001) and induced alterations in the proliferative pattern and crypt morphometrics in the colonic epithelium of both mouse strains. While C57BL/6J mice developed a greater number of aberrant crypt foci than BALB/cJ mice (p less than 0.0001), a significant diet-strain interaction effect was not observed. The present results indicate that dietary cholesterol enhances the induction and development of chemically-induced colonic precancerous lesions but this process is not affected by genetic differences in cholesterol metabolism, as represented by the two strains of mice studied.

Animals↗
PubMed1993

Alpha 1-antitrypsin as a biomarker in azoxymethane induced intestinal tumors in F344 rats.

Alpha 1-antitrypsin (alpha 1AT) has been detected in several human tumors and is thought to be a marker of neoplastic change and progression. As the biology of azoxymethane (AOM) induced intestinal tumors in F344 rats has many characteristics of human intestinal tumors, we have investigated alpha 1AT expression in AOM induced rat intestinal tumors. Nine of 12 colonic carcinomas and 6/8 small intestinal carcinomas had alpha 1AT positive tumor cells. Only 1/11 colonic adenomas and 0/3 small intestinal adenomas contained alpha 1AT. Thus alpha 1AT is a marker of malignancy in this model. Inhibition of carcinogenesis by piroxicam and difluoromethyl ornithine inhibited alpha 1AT expression.

Adenocarcinoma↗