Effect of dietary oxidized cholesterol on azoxymethane-induced colonic preneoplasia in mice.

The effect of cholesterol and oxidized cholesterol on azoxymethane-induced colonic preneoplasia was evaluated in C57BL/6J and BALB/cJ mouse strains. Mice were fed either a control AIN 76 semisynthetic diet or the control diet supplemented with 0.1% or 0.3% cholesterol, or 0.1% or 0.3% oxidized cholesterol for an 8-week period. For the first 4 weeks of the experiment, mice received weekly injections of azoxymethane (5 mg/kg body weight). Dietary cholesterol increased fecal concentrations of neutral and acid sterols. A dose-response relationship was observed in both mouse strains between the level of dietary cholesterol or oxidized cholesterol and formation of preneoplastic aberrant crypt foci. Enhanced cell proliferation along with alterations in several crypt morphometric parameters were also observed. These anomalies were enhanced to a greater extent by oxidized cholesterol. This data shows a very strong effect of cholesterol in enhancing the development of preneoplastic lesions in chemically induced cells. It also demonstrated that the state of oxidation of cholesterol influences colonic preneoplasia. This factor has been overlooked in previous animal experiments.     

Foreign-body tumors of mice: strain and sex differences in latency and incidence.

Sarcomas were induced by sc implantation of unplasticized polyvinylchloride acetate films in female and male mice of strains AKR/J, BALB/cJ, BALB/cWat, CBA/H and CBA/H-T6, C3H/HeJ, C57BL/10ScSn, C57BL/6J-bgj, C57BL/cdJ, DBA/-1J l/LnJ, LP/J, SJL/J, X/Gf, 129/J, and hybrids (CBA/H-T6 X AKR/J)F1, (C57BL/10ScSn x CBA/H or CBA/H-T6)F1, (C57BL/6J-bgj x C57BL/6J)F1. The strains and sexes showed marked differences in incidence and mean latency of resulting tumors. Crucial information was provided for the selection of appropriate mouse strains for the study of interrelationships between genotypes, defined somatic properties, and the multifactorial process of foreign-body tumorigenesis.     

A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility

Lung cancer, primarily associated with tobacco use, is the leading cause of cancer morbidity and mortality in the United States. Squamous cell carcinoma (SCC) is one of the four major histological types of lung cancer. Although there are several established models for lung adenoma and adenocarcinomas, there is no well-established mouse model for lung SCC. We treated eight different inbred strains of mice with N-nitroso-tris-chloroethylurea by skin painting and found that this regimen induced lung SCCs in five strains of mouse (SWR/J, NIH Swiss, A/J, BALB/cJ, and FVB/J) but not in the others (AKR/J, 129/svJ, and C57BL/6J). Mouse lung SCCs have similar histopathological features and keratin staining to human SCC. Moreover, a wide spectrum of abnormal lung squamous phenotypes including hyperplasia, metaplasia, carcinoma in situ, and invasive carcinoma, were observed. There are strain-specific differences in susceptibility to Lscc induction by N-nitroso-tris-chloroethylurea with NIH Swiss, A/J, and SWR/J mice developing scores of SCCs whereas the resistant strains AKR/J, 129/svJ, and C57BL/6J failed to develop any SCCs. FVB/J and BALB/cJ mice had an intermediate response. We conducted whole-genome linkage disequilibrium analysis in seven strains of mice, divided into three phenotype categories of susceptibility, using Fisher's exact test applied to 6,128 markers in publically available databases. Three markers were found significantly associated with susceptibility to SCC with the P < 0.05. They were D1Mit169, D3Mit178, and D18Mit91. Interestingly, none of these sites overlap with the major susceptibility loci associated with lung adenoma/adenocarcinoma development in mice. The mouse SCC described here is highly significant for preclinical studies of lung cancer chemopreventive agents because most human trials have been conducted against precancerous lesions for SCC. Furthermore, this model can be used in determining genetic modifiers that contribute to susceptibility or resistance to lung SCC development.     

The suppression of aberrant crypt multiplicity in colonic tissue of 1,2-dimethylhydrazine-treated C57BL/6J mice by dietary flavone is associated with an increased expression of Krebs cycle enzymes

Colorectal cancer is the second leading cause of cancer deaths worldwide with diet playing a prominent role in disease initiation and progression. Flavonoids are secondary plant compounds that are suggested as protective ingredients of a diet rich in fruits and vegetables. We here tested whether flavone, a flavonoid that proved to be an effective apoptosis inducer in colon cancer cells in culture, can affect the development of aberrant crypt foci (ACFs) in C57BL/6J mice in vivo when preneoplastic lesions were induced by the carcinogen 1,2-dimethylhydrazine (DMH). Flavone applied at either a low dose (15 mg/kg body wt per day) or a high dose (400 mg/kg body wt per day) reduced the numbers of ACFs significantly, independent of whether it was supplied simultaneously with the carcinogen (blocking group) or subsequent to the tumor induction phase (suppressing group). Proteome analysis performed in colonic tissue samples revealed that flavone treatment increased the expression of a number of Krebs cycle enzymes in the suppressing group and this was associated with reduced crypt multiplicity. It suggests that mitochondrial substrate oxidation is increased by flavone in colonic cells in vivo as already observed in HT-29 cells in vitro as the prime mechanism underlying tumor cell apoptosis induction by flavone. In conclusion, flavone reduces the number of ACFs in DMH-treated mice at doses that can be achieved for flavonoids by a diet rich in fruits and vegetables. Moreover, reduction in crypt multiplicity by flavone is most probably due to the preservation of a normal oxidative metabolism.     

Androgen receptor-mediated genetic differences in 2-acetylaminofluorene and dimethylnitrosamine mutagenesis in vitro

When 2-acetylaminofluorene and dimethylnitrosamine mutagenesis rates in the Salmonella/liver in vitro system were studied with C3H/HeJ mouse kidney or liver postmitochondrial supernatant (S-9) fractions, sex differences (male much greater than female) of 10- to 30-fold were found in kidney but not liver. We examined male mice castrated during the neonatal period, the Tfm/Y male, and dihydrotestosterone-treated female mice. The requirement of both testosterone and the androgen receptor is shown to be important in causing the sex difference in 2-acetylaminofluorene and dimethylnitrosamine mutagenesis in the kidney. Swank et al. [J Mol Biol 81:225-243 (1973)] demonstrated that dihydrotestosterone induces beta-glucuronidase activity in the female kidney: 28- to 30-fold in BALB/cJ and SM/J, 12-fold in C3H/HeJ, and 5- to 6-fold in C57BL/6J and RF/J inbred mice. This gene regulation has been characterized and named the Gur locus. 2-Acetylaminofluorene mutagenesis--in kidney but not liver--is markedly enhanced by dihydrotestosterone (P less than 0.01) in the first three, but not the latter three, inbred strains. Covalent binding of 2-acetylaminofluorene metabolites to DNA in the presence of kidney S-9 fractions in vitro is greatly increased in the BALB/cJ but not C57BL/6J female mouse pretreated with dihydrotestosterone. These data suggest that genetic differences at the Gur locus, in combination with the androgen receptor, may play an important role in the sex-specific and tissue-specific conversion of an O-glucuronide of N-hydroxy-2-acetylaminofluorene or N-hydroxy-aminofluorene to active mutagenic intermediates.     

Risk of Colonic Cancer is Not Higher in the Obese Lepob Mouse Model Compared to Lean Littermates

Epidemiological data suggest that obesity increases the risk of colorectal cancer in humans. Given that diet-induced obesity mouse models verified the epidemiological data, the present study aimed to determine whether obese C57BL/6J-Lep^ob male mice (a different obesity in vivo model) were at greater risk of colonic cancer than their lean male littermates. Risk of colonic tumorigenesis was assessed by numbers of aberrant crypts, aberrant crypt foci and colonic tumors. Proliferation of the colonic epithelia was assessed histochemically following administration of BrdU. Availability of the procarcinogen, azoxymethane (AOM) to target tissues was assessed by quantifying via HPLC plasma AOM concentrations during the 60 min period following AOM injection. When obese and lean mice were injected with azoxymethane (AOM) at doses calculated to provide equivalent AOM levels per kg lean body mass, obese animals had significantly fewer aberrant crypts/colon and fewer aberrant crypt foci/colon than the lean animals. Tumors were identified in the colonic mucosa of lean (4 tumors in 14 mice) but not obese (0 tumors in 15 mice) mice. Colonic cell proliferation was not significantly different for obese and lean mice. Because these results were unexpected, plasma AOM concentrations were measured and were found to be lower in the obese than lean mice. When plasma AOM levels were comparable for the lean and obese mice, the Lep^ob mice continued to have significantly fewer aberrant crypt foci/colon than the lean mice, but differences were not statistically different for aberrant crypts/colon. Interestingly, obese Lep^ob mice did not exhibit increased risk of colonic cancer as expected. Instead, Lep^ob mice exhibited equivalent or lower risk of colon cancer when compared to the lean group. These results taken together with in vivo results from diet-induced obesity studies, imply that leptin may be responsible for the increased risk of colon cancer associated with obesity.     

Identification of an X-linked locus modifying mouse skin tumor susceptibility

The enhancing effect of overexpression of an ornithine decarboxylase (Odc) transgene on skin tumor susceptibility can be modified by genetic loci present in several inbred mouse strains. The BALB/cJ strain is among the most resistant strains so far examined; tumor multiplicity following 7,12-dimethylbenz(a)anthracene (DMBA) treatment is reduced by 90% when the K6/ODC transgene is expressed on a BALB/cJ background versus the susceptible C57BL/6J background. Further, transgenic BALB/cJ males developed more tumors than females, indicating the presence of sex-dependent modifier pathway. Analysis of 263 F2 intercross mice revealed significant linkage of markers on the X chromosome to tumor multiplicity. This analyses as well as a similar genome-wide scan of 136 backcross mice found evidence for other modifier loci on chromosomes 4, 6, and 17. Identification of these modifier genes should reveal the effector pathways responsive to Odc overexpression that mediate susceptibility to skin tumorigenesis.     

High susceptibility to azoxymethane-induced colorectal carcinogenesis in obese KK-Ay mice

Obesity is associated with colon carcinogenesis. However, not much information is available regarding the mechanisms of obesity-associated colorectal cancer, and there are only few useful animal models for investigating the underlying mechanism between obesity and colorectal cancer. KK-A(y) mice exhibit severe obesity. Amount of visceral fat assessed by micro-computed tomography was almost 15 times higher than that of same aged C57BL/6J mice. Treatment with azoxymethane (AOM; 200 μg/mouse injected once a week for 3 times) resulted in markedly increased colon aberrant crypt foci (ACF) development (≈70 ACF/mouse) in KK-A(y) mice compared with lean C57BL/6J mice (≈9 ACF/mouse). Moreover, administration of AOM at a dose of 200 μg/mouse once a week for 6 times developed colorectal adenocarcinomas within only 7 weeks after the last AOM injection. The incidence of adenocarcinoma was 88% in KK-A(y) mice and was markedly higher than the 4% observed in C57BL/6J mice. The number of tumors/mouse was 7.80 in KK-A(y) mice and also markedly higher than the 0.12 in the C57BL/6J case. Interestingly, adenocarcinomas were observed in most of the AOM-treated KK-A(y) mice along with remarkable tumor angiogenesis, and some showed submucosal invasion. These results indicate that the KK-A(y) mouse, featuring intact leptin and leptin receptor Ob-Rbl, could be a useful animal model to investigate obesity-associated cancer.     

Major effect on susceptibility to urethan-induced pulmonary adenoma by a single gene in BALB/cBy mice

Fewer lung adenomas were induced by urethan in BALB/cBy mice than in the A/J or SWR/J mouse strains. When BALB mice were crossed with either of these more sensitive strains the response of the progeny to urethan was most easily explained by a single gene which regulates susceptibility, with the more resistant phenotype behaving as a dominant trait. C56BL/6J mice were more resistant to adenoma induction than were BALB mice; progeny obtained when these two strains were crossed resembled the BALB susceptibility phenotype. As an approach to understanding the mechanism of action of this gene, agents that modulate adenoma initiation and tumor promotion were tested in BALB mice and other strains. The number of adenomas in BALB mice were increased severalfold by multiple urethan injections, which presumably affect initiation, and by the use of butylated o-hydroxytoulene as a promoting agent. Tumor incidence in A-mice was increased 50% by each treatment; neither procedure caused tumors to appear in the resistant DBA/2J, C3H/-21BG, or C57BL/6J strains. No relationship was observed between the strain dependency of the lethal effects of multiple injections of these agents and the relative susceptibilities of these strains to adenoma induction. The role of certain host factors in the regulation of tumor susceptibility was also tested. Homozygosity for the beige (bg) mutation had no effect on tumor numbers in C57 mice, suggesting that natural killer cells, deficient in bg/bg mice, played no major role in determining adenoma susceptibility in this strain. No correlation was found between the susceptibility of various sublines to urethan-induced lung adenoma and the reported relative tumoricidal capacities of the peritoneal macrophages from these sublines.     

1,2-Dimethylhydrazine-induced nuclear aberrations in A/J and C57BL/6J mouse colonic crypts

A single exposure to 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8] produces several forms of aberrant nuclei in the crypts of the murine colon. The frequency of nuclear aberrations (NAs) was examined in the distal colonic crypts in DMH-sensitive A/J mice and relatively DMH-resistant C57BL/6J mice before and after a single exposure to DMH. NAs, mitotic figures, and crypt column heights were scored for all animals as a function of time following administration of DMH. In both strains there was a significant increase in the absolute and relative frequency of NAs by 12 hours, with a corresponding drop and subsequent overshoot in the mitotic index by 48 hours after DMH. The temporal changes in crypt column height correlate closely with the temporal changes in frequency of NAs in both strains. The results showed that both inbred strains respond to acute DMH exposure in a similar and parallel fashion over time. It was concluded that the NA index assay is a sensitive method for detecting early DMH exposure. However, this assay does not relate to ultimate outcome after chronic DMH exposure and should not be used as a predictor of eventual neoplastic transformation of colonic mucosa with this carcinogen.     

Tumor formation is correlated with expression of beta-catenin-accumulated crypts in azoxymethane-induced colon carcinogenesis in mice

We have reported that β-catenin-accumulated crypts (BCAC) are independent of aberrant crypt foci (ACF) in the colonic mucosa of rats exposed to colorectal carcinogens, and we suggested that they may be premalignant lesions. In the present study, we performed a comparative study on the formation of the two types of early-appearing lesions (BCAC and ACF), and tumors of the colon in two mouse strains with different susceptibility to azoxymethane (AOM). SWR/J mice are known to be relatively susceptible to AOM, whereas AKR/J mice are reported to be virtually resistant. Both AKR/J and SWR/J mice, 6 weeks old, received subcutaneous injections of AOM (15 mg/kg body weight) once a week for 3 weeks, and were sacrificed at 16 and 41 weeks of age. Colons of the animals sacrificed at 16 and 41 weeks of age were processed to examine expression of the early-appearing lesions and neoplasms. Although AKR/J mice had a lower incidence of colonic tumors than SWR/J mice did, AKR/J mice showed a similar frequency of ACF to that in SWR/J mice. In both strains, ACF were detected at high frequency in the proximal colon, whereas tumors developed mainly in the distal colon. Importantly, the incidence of BCAC in SWR/J mice was significantly higher than that in AKR/J mice, and the highest frequency was observed in the distal segments of the colon. These results support the idea that BCAC are a reliable surrogate endpoint for colon carcinogenesis in mice.     

Rapid growth of preneoplastic lesions in hepatocarcinogen-Sensitive C3H/HeJ male mice relative to C57BL/6J male mice

We have previously shown that C3H/HeJ male mice are {small tilde}20-fold more susceptible to the induction of liver tumors byN-ethyl-N-nitrosourea (ENU) than are C57BL/6J male mice andthat this difference in sensitivity is largely determined bya single genetic locus (Hcs, hepatocarcinogen sensitivity).In order to determine whether the Hcs locus affects initiationor promotion of hepatocarcinogenesis, we studied the developmentof putatively preneoplastic hepatic lesions that are deficientin glucose-6-phosphatase (G6Pase) in mice treated at 12 daysof age with ENU. In ENU-treated male mice of both strains, thenumber and size of G6Pase-deficient hepatic foci increased overtime between 12 and 24 weeks of age. However, the rate of growthof the lesions was 1.7 times faster for C3H/HeJ male mice (volumedoubling time 2.0 ± 0.1 weeks) than for C57BL/6J mice(3.4 ± 0.4 weeks). Although the number and size of G6Pase-deficientfoci induced by ENU treatment of female C3H/HeJ and C57BL/6Jmice were smaller than for foci in similarly treated male mice,there was no significant difference between the growth ratesof the foci in female C3H/HeJ and C57BL/6J mice. Thus, the phenotypiceffect of the Hcs locus appears to be dependent on promotionof liver tumor induction by the male hormonal environment. Inagreement with studies on the growth rate of the foci in malemice, the [₃H]thymidine labeling index of G6Pase-deficient hepatocytesin C3H/HeJ males (12%) was 1.5-fold higher than in C57BL/6Jmale mice (8.0%) at 20 weeks and 1.2-fold higher at 28 weeks(11% versus 9.5%). The labeling index of histochemically normalhepato cytes in C3H/HeJ male mice (0.38%) was 2.6-fold higherthan in C57BL/6J mice (0.15%) The Hcs locus may affect the promotionphase of hepatocarcinogenesis in male mice by increasing theproliferative rate of both normal and preneoplastic hepatocytes.     

Spontaneous initiation,promotion and progression of colorectal cancer in the novel A/J Min/+ mouse

The C57BL/6J multiple intestinal neoplasia (Min/+) mouse is a widely used murine model for familial adenomatous polyposis, a hereditary form of human colorectal cancer. However, it is a questionable model partly because the vast majority of tumors arise in the small intestine, and partly because the fraction of tumors that progress to invasive carcinomas is minuscule. A/J mice are typically more susceptible to carcinogen‐induced colorectal cancer than C57BL/6J mice. To investigate whether the novel Min/+ mouse on the A/J genetic background could be a better model for colorectal cancer, we examined the spontaneous intestinal tumorigenesis in 81 A/J Min/+ mice ranging in age from 4 to 60 weeks. The A/J Min/+ mouse exhibited a dramatic increase in number of colonic lesions when compared to what has been reported for the conventional Min/+ mouse; however, an increase in small intestinal lesions did not occur. In addition, this novel mouse model displayed a continual development of colonic lesions highlighted by the transition from early lesions (flat ACF) to tumors over time. In mice older than 40 weeks, 13 colonic (95% CI: 8.7–16.3) and 21 small intestinal (95% CI: 18.6‐24.3) tumors were recorded. Notably, a considerable proportion of those lesions progressed to carcinomas in both the colon (21%) and small intestine (51%). These findings more closely reflect aspects of human colorectal carcinogenesis. In conclusion, the novel A/J Min/+ mouse may be a relevant model for initiation, promotion and progression of colorectal cancer.     

Quantitative analysis of early chemically-induced pulmonary lesions in mice of varying susceptibilities to lung tumorigenesis

Inbred mice vary in their susceptibility to develop macroscopic, chemically-induced, pulmonary neoplasias. It is not known, however, whether microscopic lesions appear in resistant strains but do not grow or if no early lesions arise at all. We show herein that resistant C57BL/6J (B6) and intermediately resistant BALB/cByJ (BALB) mice form very few urethane-induced early microadenomas (i.e. adenomas larger than hyperplasic foci, but detectable only by light microscopy). Additionally, while all urethane-induced microadenomas in sensitive A/J mice gave rise to adenomas, most microscopic tumors induced in BALB mice by 2-stage, 3-methylcholanthrene/butylated hydroxytoluene carcinogenesis spontaneously regressed. The formation of microscopic lesions is thus genetically dependent, but whether they continue to grow or regress depends on how they were induced.     

Embryo-derived teratocarcinoma: I. The role of strain and gender in the control of teratocarcinogenesis

The role of gender and genetic (strain-specific) factors in the regulation of teratocarcinogenesis was studied by monitoring the outgrowth of benign and malignant embryo-derived teratoid tumors, i.e., teratomas and teratocarconomas in several mouse strains. Teratocarcinomas were produced in all mouse strains tested, but the ratio of teratoma to teratocarcinoma varied from one strain to another. A high yield of teratocarcinomas was obtained in A/J, BALB/cJ, DBA/2J, CBA/J and C3H/J mice, irrespective of the sex of the recipient. A low yield of teratocarcinomas was obtained in both male and female C57BL/6J and AKR/J recipients, and in 129/J female recipients. For all strains but 129/J and eventually AKR/J the sex of the recipients did not significantly affect the outgrowth of embryo-derived tumors. These data suggest the existence of mouse strains with high and low permissiveness for embryo-derived teratocarcinogenesis. The sex of the recipients may influence the yield of embryo-derived teratocarcinomas in some mouse strains but is of no consequence in others.     

Sucrose enhancement of the early steps of colon carcinogenesis in mice

The association of refined sugars and colorectal cancers andpolyps in three recent case-control studies led us to investigatethe effects of sucrose, fructose and glucose on colonic epithelialproliferation and sensitivity to carcinogenesis. CF1 and C57BL/6Jmice were used; proliferation was assessed as vincristine-accumulatedmitotic figures per crypt section; sensitivity to carcinogenesiswas assessed as the number of aberrant crypt foci (ACF) percolon observed following the colon carcinogen, azoxymethane(AOM, 3 mg/kg and 5 mg/kg). Oral gavages of sucrose and fructosein CF1 mice (10 g/kg) increased colonic proliferation 16 h later(2.8±0.6 and 4.1±0.7 (mean±SEM) accumulatedmitotic figures/crypt section), compared with glucose and water(1.0+0.2 and 0.4±0.1). Sucrose and fructose given 14h prior to the AOM (5 mg/kg) increased the sensitivity of thecolon to carcinogenesis (18.4±1.5 and 13.1±1.8ACF/colon), compared with glucose and water (11.4±2.0and 8.6±1.1). Similar results were observed with C57BL/6Jmice. We conclude that dietary sucrose and fructose may representrisk factors for colorectal cancer through a direct effect ofthe sugars on colonic epithelial proliferation.     

Suppression of intestinal polyps in Msh2-deficient and non-Msh2-deficient multiple intestinal neoplasia mice by a specific cyclooxygenase-2 inhibitor and by a dual cyclooxygenase-1/2 inhibitor

Epidemiological studies suggest that nonsteroidal anti-inflammatory agents decrease the risk of colorectal cancer. This is believed to be mediated, at least in part, by inhibition of cyclooxygenase (COX) activity. There are two COX isoenzymes, namely the constitutively expressed COX-1 and the inducible COX-2. COX-2 is overexpressed in adenomas and colorectal cancers, and COX-2-specific inhibitors have been shown to inhibit intestinal polyps in Apc(Delta716) mice more effectively than dual COX-1/COX-2 inhibitors such as sulindac. Various Apc knockout mice, including the multiple intestinal neoplasia (Min) mouse and the Apc(Delta716) mouse, are limited by their lack of large numbers of colonic adenomas and aberrant crypt foci, the putative precursors of large-bowel polyps and cancers. Our DNA mismatch-repair-deficient Min mouse model (Apc+/-Msh2-/-) has genetic features of both familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, and most importantly, rapidly develops numerous small- and large-bowel adenomas, as well as colonic aberrant crypt foci. The purpose of this study was to determine the effects of COX inhibitors on intestinal adenomas and colonic aberrant crypt foci in this accelerated polyposis, mismatch-repair-deficient Min mouse model, in addition to a standard Min mouse model. Weanling Apc+/-Msh2-/- and Min mice were fed diets containing no drug, sulindac, or a specific COX-2 inhibitor (MF-tricyclic). Apc+/-Msh2-/- and Min mice were sacrificed after 4 weeks and 5 months on diet, respectively. Apc+/-Msh2-/- mice treated with MF-tricyclic had significantly fewer small-bowel polyps (mean +/- SD, 178 +/- 29) compared with mice on sulindac (278 +/- 80), or control diet (341 +/- 43; P < 0.001). There was no difference in numbers of large-bowel polyps or aberrant crypt foci in mice in the three groups. MF-tricyclic was also effective in reducing both small- and large-bowel polyps in Min mice. Western analysis demonstrated COX-2 expression in both large- and small-bowel polyps from mice of both genotypes. This study demonstrates that a specific COX-2 inhibitor is effective in preventing small-bowel polyps in mismatch-repair-deficient Min mice and both small- and large-bowel polyps in standard Min mice. Therefore, specific COX-2 inhibitors may be useful as chemopreventive and therapeutic agents in humans at risk for colorectal neoplasia.     

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.