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PubMed2000

Differential expression of p16(INK4a) in azoxymethane-induced mouse colon tumorigenesis.

Alterations in the p16(INK4a) gene have been implicated in the pathogenesis of different human cancers and animal tumors. We postulated that alterations in the p16(INK4a) gene may also be involved in mouse colon tumorigenesis induced by the chemical carcinogen azoxymethane (AOM). In the present study, p16(INK4a) deletion status and its expression were examined in an AOM-induced mouse colon tumor model. Polymerase chain reaction-based deletion analysis of p16(INK4a) exon 2 showed no deletions in the colon tumors. The expression and localization of p16(INK4a) and its gene product were examined by reverse transcription-polymerase chain reaction and immunohistochemical analyses, respectively. The p16(INK4a) mRNA levels were low, and in some cases undetectable, in control colon tissue. However, colon tumors exhibited an eightfold increase in p16(INK4a) mRNA level when compared with control colon tissue (P < 0.01). Whereas control colon epithelium was uniformly negative for p16(INK4a) immunoreactivity, p16(INK4a)-immunoreactive cells were markedly increased in preneoplastic lesions and adenomas isolated from AOM-treated mice. To further examine the p16(INK4a) regulatory pathway, the retinoblastoma tumor-suppressor protein (Rb) was also examined immunohistochemically in these tissues. A heterogeneous Rb immunostaining was observed in preneoplastic lesions and adenomas. Immunohistochemical analysis also showed a reciprocal relationship between p16(INK4a) and Rb protein expression. These findings suggest that alterations in the p16(INK4a)/Rb pathway may play an important role in AOM-induced mouse colon tumorigenesis. Mol. Carcinog. 28:139-147, 2000.

Adenocarcinoma↗
PubMed2000

Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats.

Obacunone and limonin are bitter limonoids in citrus. Their modifying effects on the development of aberrant crypt foci (ACF), the activity of detoxification enzymes, glutathione S-transferase (GST) and quinone reductase (QR), and cell proliferation activity were investigated in male F344 rats treated with azoxymethane (AOM). Obacunone and limonin were administered in the diet, during the initiation (for 4 weeks) or postinitiation phase (for 4 weeks) of AOM-induced tumorigenesis. Feeding of obacunone and limonin (0.02% or 0.05%) caused significant reduction (55-65% by "initiation" feeding and 28-42% by "postinitiation" feeding) in the yield of ACF. The ability to reduce the proliferating cell nuclear antigen-labeling index in crypts and correlated well with the prevention of ACF. In a subsequent long-term experiment (38 weeks), in which rats were initiated with AOM and fed 0.05% obacunone or 0.05% limonin during the initiation or post-initiation phase, both compounds in diet caused significant reduction (65%-92% inhibition) in the incidence of colonic adenocarcinoma. Thus, citrus bitter limonoids obacunone and limonin possess chemopreventive effects on chemically induced rat colon carcinogenesis.

Animals↗
PubMed2006

Effects of quercetin and beta-carotene supplementation on azoxymethane-induced colon carcinogenesis and inflammatory responses in rats fed with high-fat diet rich in omega-6 fatty acids.

Chronic inflammation in gastrointestinal tract has been suggested as a risk factor for tumor formation. The effect of dietary supplementation of quercetin or beta-carotene on colon carcinogenesis and inflammatory response in rats fed with high-fat diet rich in omega-6 fatty acids was assessed. Animals were exposed to two weekly subcutaneous injections of AOM (azoxymethane) at a single dose of 15 mg/kg body weight. A portion of rats from each group was sacrificed at 8 weeks after the last AOM treatment to determine ACF (aberrant crypt foci) formation. Colonic mucosa expression of iNOS (inducible nitric oxide) and COX-2 (cyclooxygenase-2) protein, and blood PGE2 (prostaglandin E2) level were measured. The remaining groups of animals were sacrificed at 33 weeks after the last AOM treatment to examine colon tumor formation. Rats on high-fat diet developed more aberrant crypt foci (P<0.05) compared with those of rats on regular diet. In the same vein, but in contrast to the effect seen with regular diet, the high-fat diet induced a significant up-regulation of iNOS expression. There was no significant change in the extent of COX-2 expression or in the PGE2 levels. Quercetin or beta-carotene supplementation reduced the number of ACF only in animals fed high-fat diet (p<0.05), however, no significant difference in tumor incidence was found. At week 33, the expression of iNOS was reduced by quercetin without a statistical significance, and COX-2 expression was slightly reduced in rats on beta-carotene supplementation. No change in PGE2 levels was observed. Whilst dietary antioxidants are considered as effective suppressors for precancerous lesion formation in colons exposed to high-risk diet, it is clear that elucidating the role of individual antioxidants in colon tumor formation coupled with an understanding of the molecular mechanisms involved would benefit colon cancer prevention strategies.

Animals↗
PubMed2004

Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats.

The inhibitory effects of dietary feeding of citrus nobiletin on azoxymethane (AOM)-induced rat colon carcinogenesis using a long-term bioassay were investigated. Five-week old male F344 rats were initiated with two weekly subcutaneous injections of AOM (20 mg/kg bw) to induce colonic tumors. They were also given the diets containing 0.01% or 0.05% nobiletin for 34 weeks, starting one week after the last dosing of AOM. At the end of the study, the incidence of colonic adenocarcinoma were 67% in the AOM alone group, 55% in the AOM-->0.01% nobiletin group, 35% (p<0.05) in the AOM-->0.05% nobiletin group. Also, nobiletin feeding reduced the cell-proliferation activity, increased the apoptotic index, and decreased the prostaglandin E2 content in colonic adenocarcinoma and/or colonic mucosa. These findings might suggest that citrus nobiletin has chemopreventive ability against AOM-induced rat colon carcinogenesis.

Animals↗
PubMed2004

Intestinal expression of mutant and wild-type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice.

BACKGROUND: The authors recently reported that transgenic mice (hGAS) expressing pharmacologic levels of progastrin (PG) (> 10 nM to 100 nM) exhibited increased susceptibility to colon carcinogenesis in response to azoxymethane (AOM). It is not known whether PG functions as a cocarcinogen at the concentrations observed in patients with hypergastrinemia (approximately 1.0 nM). METHODS: The authors generated transgenic mice that overexpressed either wild-type (wtPG) or mutant (mtPG) human PG in the intestinal mucosa using the murine fatty acid binding protein (Fabp) promoter. Fabp-PG mice and their wild-type littermates were treated with AOM, and their colons were examined for preneoplastic (aberrant crypt foci [ACF]) and neoplastic (adenomas [Ads] and adenocarcinomas [AdCas]) lesions after 2 weeks and 6 months of treatment. RESULTS: ACF and tumors were significantly more common (by a factor of approximately 2) in colon specimens from both Fabp-wtPG mice and Fabp-mtPG mice relative to wild-type mice. It is noteworthy that the multiplicity of ACF and the total number of small and large Ads and AdCas were significantly greater in colon specimens from Fabp-PG mice compared with colon specimens from wild-type mice, irrespective of gender. CONCLUSIONS: The results of the current study suggest that at concentrations (approximately 1.0 nM) far lower than the ones observed in hGAS mice, PG functions as an equally potent cocarcinogen and significantly increases the risk of colon carcinogenesis in response to AOM. Thus, PG may represent a clinically relevant target molecule in patients with hypergastrinemia or colon carcinoma.

Animals↗
PubMed2004

Studies with the azoxymethane-rat preclinical model for assessing colon tumor development and chemoprevention.

During recent years, multidisciplinary studies in epidemiology and molecular biology have contributed to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and consumption of diets rich in omega (omega)-3 fatty acids (n-3 PUFAs) or the regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. The development of strategies for the chemoprevention of colorectal cancer have been facilitated by the use of relevant animal models mimicking the neoplastic processes that occur in humans, including similarities in histopathology and molecular and genetic lesions during both the early and promotion/progression stages of carcinogenesis. Studies with the azoxymethane-F344 rat model indicate that diets rich in n-3 PUFAs, NSAIDs, selective cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) inhibitors, and curcumin can reduce the incidence of colon cancer. Advances in the knowledge of the mechanisms by which chemopreventive agents act offer opportunities to use combinations of specific chemopreventive agents, having clinically beneficial aggregate activity with minimal toxicity. This approach is extremely important when a promising chemopreventive agent demonstrates apparent efficacy but may produce toxic effects at high doses. Our studies show that a combination of very low doses of piroxicam (NSAID) and difluoromethylornithine, a specific inhibitor of ornithine decarboxylase, or very low doses of COX-2 and HMG-CoA reductase inhibitors are more effective in inhibiting colon carcinogenesis than administration of these compounds as single agents even at higher levels. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance is to identify whether the molecular targets that are critical in the growth and survival of the malignant colorectal cell are modulated by n-3 PUFAs, NSAIDs, or COX-2 and iNOS inhibitors.

Animals↗
PubMed2004

Intake of beer inhibits azoxymethane-induced colonic carcinogenesis in male Fischer 344 rats.

Modulatory effects of beer consumption on azoxymethane (AOM)-induced rat colonic carcinogenesis in male Fischer 344 rats were investigated. Single cell gel electrophoresis assay indicated that DNA damage of colonocytes, induced by a single AOM injection (15 mg/kg body weight), was significantly reduced in rats fed beer or malt extract for 2 weeks. Examination of aberrant crypt foci (ACF) formation in colonic mucosa, induced by AOM (15 mg/kg body weight; twice weekly), revealed that feeding of beer during the whole experimental period of 5 weeks significantly reduced the number of ACF by 35%. In the post-initiation protocol, a reduction in ACF formation by 26% was not significant. The efficacy in inhibition of ACF formation varied with the brand of beer. ACF formation was significantly reduced in rats treated with freeze-dried beer (FD Beer), but not with ethanol, suggesting that nonvolatile components of beer are responsible for the reduction. Significant suppression of ACF formation was observed in groups treated with hot water extract of malt, especially with extracts of colored malts, although no reduction was observed by feeding with hops extract. A long-term experiment of 42 weeks indicated that intake of beer decreased tumor incidence by 22% and decreased the number of neoplastic lesions, including adenocarcinomas and adenomas, by 44%. These results suggest that components of beer have chemopreventive effects on colonic carcinogenesis induced by AOM and that intake of beer may contribute to a reduction in the risk of cancer susceptibility.

Adenocarcinoma↗
PubMed2004

Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane-induced rat colon carcinogenesis through elevation of colonic PPARgamma expression and alteration of lipid composition.

Our previous short-term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in cis(c)9, trans(t)11, t13-conjugated linolenic acid (CLN), inhibited the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In our study, the possible inhibitory effect of dietary administration of BMO on the development of colonic neoplasms was investigated using an animal colon carcinogenesis model initiated with a colon carcinogen AOM. Male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce colon neoplasms. They also received diets containing 0.01%, 0.1% or 1% BMO for 32 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (32 weeks), AOM induced 83% incidence (15/18 rats) of colonic adenocarcinoma. Dietary supplementation with 0.01% and 0.1% BMO caused significant reduction in the incidence (47% inhibition by 0.01% BMO, p<0.02; 40% inhibition by 0.1% BMO, p<0.05; and 17% inhibition by 1% BMO) and the multiplicity (64% inhibition by 0.01% BMO, p<0.005; 58% inhibition by 0.1% BMO, p<0.02; and 48% inhibition by 1% BMO, p<0.05) of colonic adenocarcinoma, though a clear dose response was not observed. Such inhibition was associated with the increased content of CLA (c9,t11-18:2) in the lipid composition in colonic mucosa and liver. Also, BMO administration in diet enhanced expression of peroxisome proliferator-activated receptor (PPAR) gamma protein in the nonlesional colonic mucosa. These findings suggest that BMO rich in CLN can suppress AOM-induced colon carcinogenesis and the inhibition might be caused, in part, by modification of lipid composition in the colon and liver and/or increased expression of PPARgamma protein level in the colon mucosa.

Adenocarcinoma↗
PubMed2005

Absence of acute apoptotic response to genotoxic carcinogens in p53-deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumours.

Acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the consequences of mutational load in the colon. It has been shown to occur in parallel with activation of DNA repair mechanisms. Inadequate AARGC might allow development of mutated clones with the potential to progress to cancer. In this study, we tested if p53 levels were important for AARGC in the colon and whether defective AARGC was associated with increased risk for colorectal oncogenesis. Apoptosis was measured in colonic epithelium of mice from each p53 genotype (p53-/-, p53+/-, wild-type) without and 8 hr following a single injection of azoxymethane (AOM). To determine risk for carcinogen-induced colorectal cancer (CRC), groups of mice from each p53 genotype received 3 weekly injections of AOM and colons were examined for tumour 20 weeks later. Rates of spontaneous apoptosis in colon were not affected by p53 level. However, AARGC was absent in p53-/- mice and reduced by 50% in p53+/- mice (both p < 0.01) compared to wild-type mice. AOM induced tumours in 30% of wild-type mice (average multiplicity 1.0 tumours/mouse) compared to 72% of p53+/- mice (2.0 tumours/mouse, p < 0.01) and 100% of p53-/- mice (2.8 tumours/mouse, p < 0.01). Without AOM, significantly fewer mice in all groups had tumours. Rates of apoptosis in tumours were independent of p53 status. p53 dysfunction puts intestinal epithelia at increased risk of genotoxin-induced oncogenesis due to impairment of apoptotic response mechanisms. p53 levels do not appear, however, to be important for spontaneous apoptosis in normal epithelium or apoptosis in tumours. Subsequent studies are now warranted to test the converse, namely, that enhanced apoptotic response to carcinogen reduces risk for colorectal oncogenesis.

Animals↗
PubMed2005

Sulindac corrects defective apoptosis and suppresses azoxymethane-induced colonic oncogenesis in p53 knockout mice.

The acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the subsequent colonic mutational load and progression through oncogenesis. We have found previously that AARGC is p53-dependent with a gene-dosage effect, and that decreased AARGC in p53(+/-) and p53(-/-) mice is associated with increased susceptibility to carcinogen-induced oncogenesis. We tested the ability of sulindac to reverse these defects. The effect of sulindac on azoxymethane (AOM)-induced apoptosis was measured in colonic epithelium in wild-type, p53(+/-) and p53(-/-) mice, 8 hr after a single AOM injection. Sulindac supplementation (0.5 +/- 0.1 mg/day) restored defective AARGC in p53(+/-) but not in p53(-/-) mice. For effect on colon tumor development, sulindac treatment was started at age 4 weeks in wild-type, p53(+/-) and p53(-/-) mice; three weekly AOM injections were commenced at 6 weeks of age to induce tumors. Sulindac reduced significantly tumor incidence and multiplicity in wild-type mice (17% and 0.3 tumors/mouse compared to 36% and 0.8 respectively without drug), in p53(+/-)mice (38% and 0.8 compared to 64% and 1.63) and in p53(-/-) mice (63% and 1.0 compared to 90% and 1.74). Although loss of p53 function impairs the apoptotic response to AOM-induced DNA damage, sulindac is capable of partly restoring this defect. As sulindac also reverses the increased risk of oncogenesis due to p53 dysfunction, its enhancement of the apoptotic response to initiating mutations might act to reduce mutational load driving oncogenesis. Sulindac is an effective chemopreventive agent in the presence of p53 dysfunction.

Animals↗
PubMed2006

Identification of flat dysplastic aberrant crypt foci in the colon of azoxymethane-treated A/J mice.

The role of aberrant crypt foci (ACF) as preneoplastic lesions in colon carcinogenesis is not clear. In Min/+ mice and their wild-type littermates treated with azoxymethane (AOM), we previously identified a subgroup of flat ACF that seem more immediate precursors of tumors than the classical elevated ACF. In the present study, we identified a similar subgroup of flat ACF in AOM-treated A/J mice and compared them with nascent tumors and classical elevated ACF. At week 1 and 2 after birth, A/J mice were injected subcutaneously with AOM (10 mg/kg bw/injection). At weeks 7-14, we examined the luminal surface of unsectioned colon preparations stained with methylene blue in the inverse light microscope. The lesions were also examined by histopathology and immunohistochemistry. Surface examination revealed flat ACF, classical elevated ACF and nascent tumors. Since flat ACF were not observed as elevated structures, their bright blue appearance and compressed pit pattern of crypt openings seen with transillumination were used as criteria for their identification. Flat ACF and nascent tumors displayed a uniform picture of severe dysplasia, compressed pit pattern, overexpression of cytoplasmic/nuclear beta-catenin and nuclear overexpression of cyclin D1. Apparently, flat ACF and tumors represented the same type of dysplastic lesions at different stages of crypt multiplication. In contrast, classical elevated ACF did not seem to be as clearly related to tumorigenesis. They infrequently (1/20) possessed severe dysplasia, overexpression of cytoplasmic/nuclear beta-catenin, or nuclear overexpression of cyclin D1, and they did not have compressed crypt openings. Furthermore, flat ACF grew significantly faster than classical elevated ACF. In conclusion, our data indicate a development from flat ACF to adenoma characterized by aberrant activation of the Wnt signaling pathway and fast crypt multiplication. Classical elevated ACF do not seem to be as closely related to tumorigenesis.

Animals↗
PubMed1989

Tissue norepinephrine depletion as a mechanism for cysteamine inhibition of colon carcinogenesis induced by azoxymethane in Wistar rats.

The effects of cysteamine (2-aminoethanethiol hydrochloride) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the norepinephrine concentration in the colon wall tissue and the labelling indices of colon mucosa and colon cancers were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and alternate-day subcutaneous injections of 25 mg/kg of cysteamine in 0.9% NaCl solution until the end of the experiment. At week 40, prolonged administration of cysteamine significantly reduced the incidence and number of colon tumors. Histologically, the adenocarcinomas that did develop in rats treated with cysteamine exhibited high mucin-producing activity. Administration of cysteamine caused significant decreases in the norepinephrine concentration in colon tissue and in the labelling indices of colon mucosa and cancers. Our findings indicate that cysteamine inhibits the development of colon tumors. This action may be related to its effect in decreasing norepinephrine concentration in the colon wall tissues and subsequently in decreasing proliferation of colon cancer cells.

Adenocarcinoma↗
PubMed1990

Enhancement of azoxymethane-induced colon carcinogenesis in spontaneously hypertensive rats.

The incidence, number, location, and histological types of colon tumors induced by azoxymethane (AOM) and the tissue norepinephrine concentration of the colon wall were investigated in spontaneously hypertensive (SH) rats and in control normotensive Wistar Kyoto (WKY) rats. All rats received 10 weekly s.c. injections of AOM. At week 30, the incidence of colon tumors were significantly higher in SH than in WKY rats. Colon tumors were chiefly located in the proximal colon in WKY but were found with significant frequency in the distal colon in SH rats. The colon tumors induced were mainly adenocarcinomas, but no significant difference in histological type of adenocarcinoma was found between the 2 strains of rat. At weeks 8 and 30, the norepinephrine concentration and labelling index of the distal colon, but not of the proximal colon, were significantly higher in SH than in WKY rats. These findings indicate that increased sympathetic nervous system activity enhances the development of colon tumors.

Adenocarcinoma↗
PubMed1992

Enhanced induction of colon carcinogenesis by azoxymethane in Wistar rats fed a low-protein diet.

The effects of ad libitum feeding of synthetic, low-protein diets on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), on the norepinephrine concentration in the colon wall tissue and on the labelling index of colon mucosa were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and were given synthetic diets of equal calorie content containing 25% casein (normal-protein diet), 10% casein (low-protein diet) or 5% casein (very-low-protein diet). Administration of the low- and very-low-protein diets resulted in significant increases in the incidence and number of colon tumors at week 30. However, it did not affect the histology of the colon tumors. The low- and very-low-protein diets also resulted in significant increases in norepinephrine concentration in the proximal and distal portions of the colon wall and in the labelling indices of both parts of the colon mucosa. Our findings indicate that low- and very-low-protein diets enhance colon carcinogenesis and that this may be related to their effects in increasing the norepinephrine level in the colon wall and in stimulating proliferation of colon epithelial cells.

Adenocarcinoma↗
PubMed1992

Inhibition of azoxymethane-induced experimental colon carcinogenesis in Wistar rats by 6-hydroxydopamine.

The effects of 6-hydroxydopamine (6-OHDA) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on norepinephrine (NE) concentration in the colon wall and the labelling index of the colon mucosa were investigated in Wistar rats. Rats received sub-cutaneous (s.c.) injections of AOM once a week for 10 weeks, and throughout 35 weeks were also given intraperitoneal (i.p.) injections of 6-OHDA. Prolonged administration of 6-OHDA was found to cause a significant reduction in the incidence and number of colon tumors. However, it had no influence on the histological features or depths of involvement of colon tumors and/or adenocarcinomas. Its administration also caused significant decreases in the NE concentration in the colon wall and in the labelling index of the colon mucosa. Our findings indicate that 6-OHDA has a protective effect against colon carcinogenesis, and that the activity of the sympathetic nervous system may have an important influence on colon carcinogenesis.

Adenocarcinoma↗
PubMed1992

Enhancement by bombesin of colon carcinogenesis and metastasis induced by azoxymethane in Wistar rats.

The effects of bombesin on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on their metastases to the peritoneum and/or lymph nodes, were investigated in Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, and s.c. injections of bombesin in depot form every other day until the end of the experiment in week 30. Administration of bombesin significantly increased the incidence of colon tumors in week 30. It had no influence on the histological features or depths of involvement of colon adenocarcinomas, but significantly increased the incidence of cancer metastasis to the peritoneum and/or lymph nodes. It also caused a significant increase in the labeling index of the colon epithelial cells. Our findings indicate that bombesin enhances the development and metastasis of colon tumors, and that this effect may be related to its effect in increasing proliferation of epithelial cells of the colon.

Adenocarcinoma↗
PubMed1992

Enhancement by thyroxine of experimental carcinogenesis induced in rat colon by azoxymethane.

The effect of thyroxine (T4) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the labeling index of colon mucosa were investigated in Wistar rats. Rats were given AOM by injection once a week for 10 weeks, together with T4 in depot form until the end of the experiment. Administration of T4 resulted in a significant increase in the incidence of colon tumors in week 35. However, it did not influence the histological appearance of the colon tumors or the histological types and depths of involvement of colon adenocarcinomas. Furthermore, it caused a significant increase in the labeling index of the colon during, but not after, AOM treatment. Our findings indicate that T4 enhances the development of colon tumors, which may be related to its effect in increasing proliferation of epithelial cells in the colon mucosa during administration of the carcinogen.

Adenocarcinoma↗
PubMed1993

Effects of all-trans retinoic acid as a potential chemopreventive agent on the formation of azoxymethane-induced aberrant crypt foci: differential expression of c-myc and c-fos MRNA and protein.

The main objectives were to determine the modulating effects of all-trans retinoic acid on the number, size and multiplicity of aberrant crypt foci as well as the in vivo expression of the genes c-myc and c-fos. These foci, which are hypothesized to be the pre-malignant lesions of colon cancer, were induced in Sprague-Dawley rats with a single injection of azoxymethane. Rats were fed either a control diet (AIN-76) or the control diet to which had been added 75 mg/kg or 150 mg/kg all-trans retinoic acid. Within 4 weeks, we observed that the diets containing all-trans retinoic acid reduced the total number and multiplicity of aberrant crypt foci in the colon. However, all-trans retinoic acid increased the size of the lesions that persisted, possibly due to a greater proportion of lesions with dilated crypts. In situ hybridization and immunohistochemistry were performed on the colons for the in vivo analysis of gene expression in these lesions. The expression of myc-specific mRNA and protein in aberrant crypt foci significantly decreased with both levels of all-trans retinoic acid. In contrast, fos-specific mRNA and protein in aberrant crypt foci significantly increased when 150 mg/kg all-trans retinoic acid was added to the diet. The most important findings of this investigation are that intervention with all-trans retinoic acid in the pre-malignant stage of colon carcinogenesis is effective in decreasing the number and growth of aberrant crypt foci and altering the expression of the c-myc and c-fos genes.

Animals↗