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PubMed2006

Mouse genetic models in alcohol research.

Animal models offer several advantages for the study of complex human disorders such as alcoholism. No animal model replicates all aspects of alcoholism but different components of the disorder can be investigated using various rodent models. In this article, we review a select subset of the most widely used mouse genetic models in alcohol research. Different genetically defined strains and stocks of mice are useful for genetic, physiologic, behavioral and pharmacological studies of this devastating disorder. In the past decade, numerous genomic regions associated with a tendency for various behavioral components of alcoholism have been identified; recent applications of new methods are shedding light on quantitative trait genes. Many of the underlying genes should be identified in the near future.

Alcoholism↗
PubMed2004

Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus.

PURPOSE: More than one third of patients with epilepsy have inadequate control of seizures with drug therapy, but mechanisms of intractability are largely unknown. Because of this large number of pharmacoresistant patients with epilepsy, the existing process of antiepileptic drug (AED) discovery and development must be reevaluated with a focus on preclinical models of therapy-resistant epilepsy syndromes such as mesial temporal lobe epilepsy (TLE). However, although various rodent models of TLE are available, the pharmacoresponsiveness of most models is not well known. In the present study, we used a post-status epilepticus model of TLE to examine whether rats with spontaneous recurrent seizures (SRSs) differ in their individual responses to phenobarbital (PB). METHODS: Status epilepticus was induced in Sprague-Dawley rats by prolonged electrical stimulation of the basolateral amygdala. Once the rats had developed SRSs, seizure frequency and severity were determined by continuous EEG/video recording over a 6-week period (i.e., a predrug control period of 2 weeks, followed by PB treatment for 2 weeks, and a postdrug control period of 2 weeks). PB was administered twice daily at maximal tolerated doses. RESULTS: Analysis of plasma drug concentrations showed that drug concentrations within the therapeutic range (10-40 microg/ml) were maintained in all rats throughout the period of treatment. In six (55%) of 11 rats, complete control of seizures was achieved, and another rat exhibited a >90% reduction of seizure frequency. These seven rats were considered responders. The remaining four (36%) rats showed either no response at all (n=3) or only moderate reduction in seizure frequency and were therefore considered nonresponders. Plasma drug concentrations did not differ between these two groups of rats. CONCLUSIONS: These data demonstrate that, similar to patients with epilepsy, rats with SRSs markedly differ in their individual responses to AED treatment. Pharmacoresistant rats selected by prolonged drug treatment from groups of rats with SRSs may provide a unique model to study mechanisms of pharmacoresistance and to identify novel AEDs for treating seizures of patients currently not controlled with existing therapies.

Amygdala↗
PubMed2003

Potential mechanism by which resveratrol, a red wine constituent, protects neurons.

Polyphenolic compounds, such as resveratrol, are naturally present at high concentration in grape skin, seeds, and red wine. Resveratrol is present in cis and trans isoforms and the major trans isomer is the biologically active one. Epidemiologic studies have revealed a reduced incidence of cardiovascular risk associated with consumers of red wine; this has been popularized as the French paradox. Resveratrol has been shown to have significant antioxidant properties in a variety of in vitro and in vivo models. It can reduce ischemic damage in heart ischemia reperfusion injury and also in brain ischemia/reperfusion in rodent models. Due to the high rate of oxygen consumption in the brain, and especially low levels of antioxidant defense enzymes, this organ is particularly susceptible of free radical damage. Most of the protective biological actions associated with resveratrol have been associated with its intrinsic radical scavenger properties. We have investigated the possibility of other indirect pathways by which resveratrol can exert its neuroprotective abilities. We have specifically tested whether heme oxygenase neuroprotective enzyme could be stimulated after resveratrol treatment. Using primary neuronal cultures, resveratrol was able to significantly induce heme oxygenase 1, whereas vehicle control showed no effect. No detectable toxicity was quantified. It is well established that after stroke significant levels of intracellular heme levels increase. The source of free heme comes mainly from several heme-containing enzymes. Heme (iron-protoporphyrin IX) is a pro-oxidant and its rapid degradation by heme oxygenase is believed to be protective. Moreover, the generation of heme metabolites can also have their own intrinsic cellular properties. All together, increased heme oxygenase activity by resveratrol is a unique pathway by which this compound can exert its neuroprotective actions.

Animals↗
PubMed1990

Subcellular changes of rat myocardium after treatment with amiodarone or desethylamiodarone, studied with electron microscopy.

Amiodarone, an antiarrhythmic agent, has proven to be unique in its capability to control arrhythmias unresponsive to conventional drugs. However, its association with many undesirable side effects after chronic usage has become just as clear. Chronic clinical toxicity with amiodarone is associated with intracellular lamellar or myelinoid inclusion bodies (onionoid bodies or corpora cepiformia) in various organs (i.e. skin, cornea, lung, liver, and lymph nodes). Previous study has demonstrated formation of these inclusion bodies in canine myocardium following multiple doses of amiodarone. The present study was designed to develop a more convenient animal model, and to measure the concentration of amiodarone, as well as desethylamiodarone (its major metabolite) in this rodent model. The direct role of desethylamiodarone in formation of lamellar inclusion bodies in rat myocardium was also investigated. Amiodarone (50 mg/kg) or desethylamiodarone (25 mg/kg) was injected intraperitoneally daily for a period of 14 days. Myocardial sections revealed the presence of lamellar inclusion bodies, round or oval in appearance, in the form of laminated or concentrically arranged membranes after either amiodarone or desethylamiodarone treatment. This is the first reference to the induction of these myelinoid inclusion bodies with desethylamiodarone. Myocardial tissue concentrations of amiodarone and desethylamiodarone exceeding plasma concentrations were found in the present study and indicate the capability of these compounds to easily distribute and accumulate in the myocardium.

Amiodarone↗
PubMed2000

The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson's disease, the bilaterally MPTP-treated rhesus monkey.

The propargylamine CGP 3466B prevents dopamine cell death both in vitro and in rodent models of Parkinson's disease. The present study investigates the efficacy of this compound to prevent the behavioral consequences of dopaminergic cell death in the best animal model of Parkinson's disease, the bilaterally MPTP-treated monkey. Rhesus monkeys were bilaterally treated with MPTP, using a two-step procedure: 2.50 mg MPTP was infused into the left carotid artery followed by a second bolus of 1.25 mg into the right carotid artery, 8 weeks later. Subcutaneous injection of either 0.014 mg/kg CGP 3466B (n = 4) or its solvent (distilled water; n = 4), twice daily for fourteen days, started two hours after the second MPTP infusion. A Parkinson rating scale was assessed for the evaluation of the effects. After the first MPTP treatment, the monkeys developed mild to moderate parkinsonian symptoms. The second MPTP treatment strongly increased the severity of Parkinson scores in all control monkeys, as assessed on day 3, 7, 14, 21, 28 and 35 after the second MPTP treatment. In contrast, CGP 3466B nearly completely prevented the increase of parkinsonian symptoms after the second MPTP treatment. The therapeutic effects of CGP 3466B were still present after a washout period of 3 weeks, implying that the effects were not symptomatic. These data are the first to show that the systemic administration of CGP 3466B is able to prevent the development of MPTP-induced motor symptoms in primates. This compound may have great value for inhibiting the progression of the neurodegenerative process in patients with Parkinson's disease.

Animals↗
PubMed2002

P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model.

PURPOSE: The purpose of this study was to compare the efficacy of P-selectin inhibition with standard anticoagulant and thrombolytic therapy in a rodent model of established deep vein thrombosis (DVT). METHODS: Rats underwent temporary inferior vena cava (IVC) ligation for 2 days to create a stasis-induced thrombosis. On day 2, the animals had the IVC ligature removed and received either recombinant P-selectin glycoprotein ligand-Ig (rPSGL-Ig; 4 mg/kg) intravenously, low-molecular weight heparin (LMWH; 450 IU/kg) subcutaneously, tissue plasminogen activator (tPA; 0.5 mg/kg) intravenously, combination rPSGL-Ig plus tPA, or saline vehicle. IVC segments were harvested from rats at 4 (n = 8) and 7 (n = 3) days after treatment. All treatments were given as a single dose except for daily LMWH. Evaluation included contrast venography with computer image analysis, thrombus weight/length (mass), vein wall leukocyte counts, cytokine and tissue factor analysis with enzyme-linked immunosorbent assay, and (ED1) monocyte immunohistochemical staining. Collagen was estimated with a quantitative assay. RESULTS: Contrast venography revealed that rats with both rPSGL-Ig and tPA treatment had significantly smaller thrombi as compared with controls at day 7 (0.34 +/- 0.07 cm(2) and 0.34 +/- 0.05 cm(2) versus 0.68 +/- 0.13 cm(2); P <.05). LMWH and tPA groups had significantly decreased thrombus mass at harvest compared with controls on day 4 (0.06 +/- 0.009 g/cm and 0.08 +/- 0.01 g/cm versus 0.1 +/- 0.005 g/cm; P <.05), and rPSGL-Ig showed a similar trend (P =.072). Vein wall, but not thrombus, monocytes were more numerous in those rats receiving rPSGL-Ig versus controls at day 4 (30 +/- 4 cells/5 high power fields [HPFs] versus 19 +/- 2 cells/5 HPFs; P <.05) and at day 7 (32 +/- 2 cells/5 HPFs versus 20 +/- 3 cells/5 HPFs; P <.05). rPSGL-Ig treatment was associated with significantly reduced vein wall collagen at day 7 versus controls (1.3 +/- 0.6 pg/mg versus 3.7 +/- 0.5 pg/mg; P <.05) and a trend toward lower tissue factor levels. CONCLUSION: rPSGL-Ig, LMWH, and tPA showed equal DVT resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a decrease in vein wall fibrosis, suggesting that purely accelerating DVT resolution may not decrease long-term vein scarring.

Animals↗
PubMed1998

The gamma interferon gene knockout mouse: a highly sensitive model for evaluation of therapeutic agents against Cryptosporidium parvum.

Cryptosporidiosis is a serious disease in malnourished children and in people with malignancies or AIDS. Current rodent models for evaluating drug therapy against cryptosporidiosis have many limitations, including the need for a high inoculum, the absence of symptoms resembling those seen in humans, and the need to maintain exogenous immunosuppression. We have developed a gamma interferon knockout (GKO) mouse model with which to evaluate therapies against C. parvum and have used paromomycin for evaluation of this model. The GKO model offers considerable improvements over other systems, since it requires no additional immunosuppression and adult mice can be infected with as few as 10 oocysts (compared with 10(7) for SCID mice). Infected mice develop profound gastrointestinal dysfunction due to extensive infection and severe mucosal damage involving the entire small intestine. Clinical symptoms, which include depression, anorexia, weight loss, and wasting, result in death within 2 to 4 weeks. The time of death depends on the oocyst challenge dose. Paromomycin modulated parasitological and clinical parameters in highly predictable and significant ways, including prevention of death. In addition, examination of the extensively infected gut provided an important insight into the dynamics between a specific drug treatment, its impact on the extent and the site of parasite distribution, and clinical outcome. These uniform symptoms of weight loss, wasting, and death are powerful new parameters which bring this model closer to the actual disease seen in humans and other susceptible mammalian species.

Amebicides↗
PubMed1999

Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model.

BACKGROUND: Chronic graft vascular disease (CGVD) in cardiac allografts has been defined as a slowly evolving vasculopathy unresponsive to conventional immunosuppression. We compared 4 rodent models of CGVD to evaluate the reproducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine (CSA) were then used to treat CGVD. METHODS AND RESULTS: Hearts were harvested and placed heterotopically into allogenic recipients. CGVD scores of PVG allografts from ACI recipients treated with CSA on days 1 through 10 were significantly elevated on day 90 (n=16) compared with other models (immunosuppression used): (1) Lewis to F344 recipients (CSA), (2) Brown Norway to Lewis (FK506), and (3) DA to Wistar-Firth (methylprednisolone, azathioprine, CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n=6), delayed Rapa (3 mg. kg-1. d-1 IP) reversed CGVD in PVG grafts (0.22+/-0.19 on day 90, n=6). ACI isografts showed no evidence of CGVD (n=6) at day 90. Immunohistochemistry of PVG grafts revealed perivascular infiltrates consisting of CD4(+) T cells and limited numbers of macrophages persisting up to day 90. Flow cytometry demonstrated increased levels of anti-donor antibody at day 90, which was significantly inhibited by Rapa treatment. CONCLUSIONS: PVG grafts developed a significant increase in CGVD without evidence of ongoing myocardial rejection. This CGVD appeared to be mediated by both cellular and humoral mechanisms, given CD4(+) perivascular infiltrates and increased levels of anti-donor antibody. The anti-CGVD effectiveness of Rapa during a period in which there was little myocardial cellular infiltrate supports a novel mechanism of effect such as smooth muscle or B-cell inhibition.

Animals↗
PubMed1996

[Development of a model of human renin hypertension in rats].

The effective development of human renin inhibitors meets its major obstacle in the absence of a suitable experimental rodent model and the species-specificity of human renin, exclusively cleaving its natural substrate human angiotensinogen. We have reconstructed the human renin-angiotensin system in transgenic rats over expressing the human angiotensinogen gene TGR (hAOGEN) 1623 by chronically injecting i.v. human recombinant renin. We have first established new in vitro enzyme kinetic techniques to measure the various components of the chimeric renin-angiotensin system and distinguished the two human and rat-specific pathways of generating angiotensin I by the human specific renin inhibitor Ro 42-5892 (Hoffmann-La Roche). Male heterozygous TGR had plasma levels of rat angiotensinogen of 1.2 +/- 0.2 mg Ang l/ml while the plasma levels of the transgene were 141 +/- 98 mg Ang l/ml (n = 41; not normally distributed). Transgene expression was found in the liver kidney, aorta, heart and adrenals. Four rats were infused i.v. with human recombinant renin at 50 ng/h over 9 days which chronically increased their blood pressure to > 200 mmHg while total plasma renin activity increased by a factor of 300. Rat renin disappeared form the plasma. This new model of experimental human renin-induced hypertension in rats will facilitate the screening and characterization of human renin inhibitors.

Angiotensinogen↗
PubMed2005

Folate supplementation increases genomic DNA methylation in the liver of elder rats.

The availability of folate is implicated as a determinant of DNA methylation, a functionally important feature of DNA. Nevertheless, when this phenomenon has been examined in the rodent model, the effect has not always been observed. Several reasons have been postulated for the inconsistency between studies: the rodent is less dependent on folate as a methyl source than man; juvenile animals, which most studies use, are more resistant to folate depletion than old animals; methods to measure genomic DNA methylation might not be sensitive enough to detect differences. We therefore examined the relationship between folate and genomic DNA methylation in an elder rat model with a newly developed method that can measure genomic DNA methylation sensitively and precisely. Thirty-nine 1-year-old rats were divided into three groups and fed a diet containing 0, 4.5 or 18 mumol folate/kg (folate-deplete, -replete and -supplemented groups, respectively). Rats were killed at 8 and 20 weeks. At both time points, mean liver folate concentrations increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend <0.001) and by 20 weeks hepatic DNA methylation also increased incrementally between the folate-deplete, -replete and -supplemented rats (P for trend=0.025). At both time points folate-supplemented rats had significantly increased levels of DNA methylation compared with folate-deplete rats (P<0.05). There was a strong correlation between hepatic folate concentration and genomic DNA methylation in the liver (r 0.48, P=0.004). In the liver of this animal model, dietary folate over a wide range of intakes modulates genomic DNA methylation.

Aging↗
PubMed1992

A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

Animals↗
PubMed2003

Distribution and colocalization of cholecystokinin with the prohormone convertase enzymes PC1, PC2, and PC5 in rat brain.

During posttranslational processing to generate CCK 8, pro-cholecystokinin (CCK) undergoes endoproteolytic cleavage at three sites. Several studies using endocrine and neuronal tumor cells in culture and recombinant enzymes and synthetic substrates in vitro have pointed to the subtilisin/kexin-like enzymes prohormone convertase (PC) 1, PC2, and PC5 as potential candidates for these endoproteolytic cleavages. In these experimental models, they all appear to be able to cleave pro-CCK to make the correct products. One rodent model has provided information about the role of PC2. PC2 knockout mouse brains had less CCK 8 than wild-type, although a substantial amount of CCK was still present. The degree to which CCK levels were reduced in these mice was regionally specific. These data indicated that PC2 is important for normal production of CCK but that it is not the only endoprotease that is involved in CCK processing. To evaluate whether PC1 and PC5 are possible candidates for the other enzymes involved in CCK processing, the distribution of PC1, PC2, and PC5 mRNA was studied in rat brain. Their colocalization with CCK mRNA was examined using double-label in situ hybridization. PC2 was the most abundant of these enzymes in terms of the intensity and number of cells labeled. It was widely colocalized with CCK. PC1 and PC5 mRNA-positive cells were less abundant, but they were also widely distributed and strongly colocalized with CCK in the cerebral cortex, hippocampus, amygdala, ventral tegmental area, and substantia nigra zona compacta. The degree of colocalization of the enzymes with CCK was regionally specific. It is clear that PC1 and PC5 are extensively colocalized with CCK and could be participating in CCK processing in the rat brain and may be able to substitute for PC2 in its absence. These three enzymes may represent a redundant system to ensure production of biologically active CCK.

Amino Acid Sequence↗
PubMedDate not supplied

Dietary modulation of alcohol-induced pancreatic injury.

This is a review of current progress in studies of alcohol-induced pancreatic injury using the rat intragastric ethanol infusion model. This model has been shown to reproduce the histopathologic characteristics of human ethanol-related pancreatic disease in a rodent model. A high fat liquid diet infused with ethanol potentiated the histologic and cellular effects of ethanol on the exocrine pancreas when compared to a low fat diet-ethanol infusion. Hypogranulation and apoptosis of pancreatic acinar cells are proposed as precursor lesions induced by ethanol leading to the subsequent development of acinar atrophy. A reduction in acinar cell sensitivity and responsiveness to cholecystokinin (CCK) is documented and proposed as a mechanism for the development of regressive changes through a reduction in the trophic effect of CCK.

Animals↗
PubMed1993

Induction by estradiol-17 beta of polycystic ovaries in the guinea pig.

In the present study we wished to develop a model for polycystic ovarian syndrome (PCOS) using the guinea pig, because this animal's cycle, compared to other rodent models, more closely emulates that of humans. Four silastic capsules, either empty or containing cholesterol or estradiol-17 beta, were placed subcutaneously for 48 h on Day 10 or 12 of the cycle. Vaginal smears were taken daily. Cardiac blood was drawn at various intervals. At necropsy, trunk blood was collected and ovaries were excised and analyzed histologically. Cycle length was extended over that in controls in animals treated with estradiol-17 beta (E2) on Day 12 of the cycle. Treatment with E2 resulted in an increase in serum estrogen 2 h after capsule insertion. No changes were evident in progesterone or androstenedione concentrations with treatment. Animals treated with E2 and killed late (54 days after capsule removal) showed cysts grossly (group A), while occult cysts were present in E2-treated animals killed early (17 days; group B); no cysts were observed in control groups. Ovarian weight and size were increased in group A over controls. There was an increase in the fraction of atretic:total follicles < 500 mm in size in group A compared to group B as well as compared to controls. Since these results are similar to those seen in human PCOS, we conclude that the guinea pig may serve as an exceptional and unique model for the study of PCOS and may be applicable to humans.

Animals↗
PubMed1993

GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion.

GLUT2 underexpression has been reported in the beta-cells of Zucker diabetic fatty rats and db/db mice, models of spontaneously occurring NIDDM with antecedent obesity. To determine whether the beta-cells of a nonobese rodent model of NIDDM exhibit the same abnormalities in GLUT2, we studied Goto-Kakizaki rats. In these mildly diabetic animals glucose-stimulated insulin secretion was reduced at all ages examined from 8 to 48 wk. In normal control Wistar rats, immunostainable GLUT2 was present on all insulin-positive cells in the pancreatic islets. Only 85% of beta-cells were GLUT2-positive in GK rats at 12 wk of age, and only 34% were positive at 48 wk of age. GLUT2 mRNA was 50% of normal in 12-wk-old GK rats. In the latter age-group, glucose-stimulated insulin secretion was only 28% of normal at a time when 85% of beta-cells were GLUT2-positive and initial 3-O-methyl-D-glucose transport rate was 77% of the control value. We conclude that although GLUT2 is underexpressed, neither the magnitude of the underexpression of GLUT2 nor of the reduction in GLUT2 transport function in islets of GK rats is sufficient by itself to explain the profound reduction in glucose-stimulated insulin secretion.

Aging↗
PubMed1999

Quantitative genetics of energy balance--lessons from animal models.

Evidence for quantitative genetic variation in components of energy balance in animals is overwhelming. Much of this evidence is drawn from livestock species and relevant rodent models, especially long-term selection lines. This mini-review summarizes findings from several animal studies that have characterized quantitative genetic variation in energy intake and energy expenditure. Applications of this information toward understanding and treatment of human obesity are explored.

Animals↗
PubMed1993

The introduction of activated oncogenes to mammary cells in vivo using retroviral vectors: a new model for the chemoprevention of premalignant and malignant lesions of the breast.

Breast cancer is an important disease site for chemopreventive intervention. The current in vivo rodent models for breast cancer do not adequately approximate the human disease. Thus, we developed a new series of models based on the direct introduction of activated oncogenes into in situ mammary ductal cells in the rat. So far we have introduced both activated ras and neu into the mammary parenchyma of the rat. Both oncogenes cause the development of mammary carcinomas without any additional exogenous intervention. The activated neu gene is, however, 200 times more penetrant than the activated ras gene. The carcinomas induced by both genes are more aggressive than those induced by chemical carcinogens. They are more often transplantable, locally invasive, and metastatic. Tumors arising from the introduction of the neu oncogene have a greater histopathological resemblance to human breast cancers than those associated with ras insertion. For example, within a week post-introduction of neu, lesions resembling ductal carcinomas in situ are observed in the rat mammary gland. These do not occur following ras introduction or exposure to chemical carcinogens. These models are helping to better define the cellular and molecular events associated with the multistage progression of breast cancer. They are also being used to develop models to evaluate chemopreventive approaches for breast cancer. For example, in the area of cancer prevention we have shown that hormonal intervention is more effective in preventing neu-initiated breast cancers than ras-initiated breast cancers. We have also shown that the chemopreventive monoterpene, d-limonene, can prevent ras-induced mammary tumors in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice.

Nonsteroidal anti-inflammatory drugs decrease sporadic colorectal carcinoma and adenomas in patients with familial adenomatous polyposis and in rodent models of sporadic colon cancer and familial adenomatous polyposis. Similarly, selective cyclooxygenase 2 inhibitors decrease adenomas in humans and rodents. However, their effects on chronic colitis and colitis-associated neoplasia are unknown. Interleukin 10-/- mice (C57/B6) were fed regular chow (n = 20) or chow with celecoxib (1,500 ppm, n = 18) or rofecoxib (75 ppm, n = 20) for 12 weeks. Twenty-eight percent of the celecoxib group died versus 5% of the control and rofecoxib groups (p < 0.05 compared with control). Celecoxib and rofecoxib increased the incidence of colitis (26% vs. 92% and 68%, p < 0.01), colitis score (0.4 +/- 0.2 vs. 2.5 +/- 0.3 and 2 +/- 0.4, p < 0.01), aberrant crypt foci (0.5 +/- 0.3 vs. 3.7 +/- 2.6 and 2.8 +/- 0.7, p < 0.01), aberrant crypts per mouse (4.11 +/- 2.1 vs. 41.2 +/- 9.7 and 27.1 +/- 7.5, p < 0.01) and dysplasia (11% vs. 54% and 42%, p < 0.01). Similarly, indomethacin (9 ppm, n = 15) increased colitis score, aberrant crypt foci, and dysplasia after 27 days of treatment. Two selective cyclooxygenase 2 inhibitors exacerbate colitis and premalignant changes in the interleukin 10-/- mouse model of chronic colitis and colitis-associated colon carcinoma.

Animals↗