Td corrigé Dear Sir - Archive ouverte HAL pdf

Dear Sir - Archive ouverte HAL

Depuis la fin du Concile Vatican II, de nombreux laïcs catholiques, qui luttent ... Heureusement, avant que le Concile soit terminé, cette vision fausse avait été corrigée et le ... venus plus tard, les frères Emili Turú, Pedro Herreros, Juan Miguel Anaya et ...... pour rechercher le pouvoir, le prestige, ou pour d'autres motivations.




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European Journal of Cancer 41 (2005) 1911–1922 – Author's version for Public Archive


How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men.

Denis E. Corpet *, Fabrice Pierre

UMR1089 Xenobiotiques, INRA & ENVT, Ecole Nationale Veterinaire Toulouse, BP-87614, 23 Capelles, 31076 Toulouse, France

Received by EJC 31 March 2005; received in revised form 13 June 2005; accepted 15 June 2005
Available online 9 August 2005

Abstract

Tumours in rodent and human colon share many histological and genetic features. To know if rodent models of colon carcinogenesis are good predictors of chemopreventive efficacy in humans, we made a meta-analysis of aspirin, beta-carotene, calcium, and wheat bran studies. Controlled intervention studies of adenoma recurrence in human volunteers were compared with chemoprevention studies of carcinogen-induced tumours in rats, and of polyps in Min (Apc(+/-)) mice: 6714 volunteers, 3911 rats and 458 mice were included in the meta-analyses. Difference between models was small since most global relative risks were between 0.76 and 1.00. A closer look showed that carcinogen-induced rat studies matched human trials for aspirin, calcium, carotene, and were compatible for wheat bran. Min mice results were compatible with human results for aspirin, but discordant for calcium and wheat bran (no carotene study). These few results suggest that rodent models roughly predict effect in humans, but the prediction is not accurate for all agents. Based on three cases only, the carcinogen-induced rat model seems better than the Min mouse model. However, rodent studies are useful to screen potential chemopreventive agents, and to study mechanisms of carcinogenesis and chemoprevention.

Keywords: Animal model; Diet; Chemoprevention; Colon-carcinogenesis; Min mice; Chemically-induced; Aspirin; b-carotene; Calcium; Wheat bran; Meta-analysis; Systematic review

1. Introduction

Some 100,000 rodents have been sacrificed on the chemoprevention altar. This number was estimated from the colon cancer chemoprevention database :
http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html
The estimate also includes liver, mammary, oesophagus, pancreas prostate, and skin cancer studies. Were these sacrifices useful? Were the time, efforts, and money needed to raise rodents, and to try to prevent their tumours of any use? The answer may seem obvious, since rodents and humans share many biological functions, and rodents are valuable for toxicity tests. Rodent studies are needed in the chemoprevention area, because epidemiological studies do not lead to firm conclusions: confusing factors cannot be fully eliminated. Thus, the hypotheses generated by epidemiology must be tested in controlled experiments, ideally in humans  ADDIN EN.CITE Hawk200557135713571317Hawk, E. T.Levin, B.Colorectal cancer preventionJ Clin OncolJ Clin Oncol378-912322005(1). But this is very long and costly, and it could jeopardize volunteers' health. Thus, animal trials should precede human trials. For instance, animal studies should have been completed before beta-carotene administration to smokers  ADDIN EN.CITE ObermuellerJevic200234533453345317ObermuellerJevic, U.C.Espiritu, I.Corbacho, A.M.Cross, C.E.Witschi, H.Lung tumor development in mice exposed to tobacco smoke and fed beta-carotene dietsToxicological SciencesToxicological Sciences23-29691PCC200220024570Forman200457345734573417Forman, M. R.Hursting, S. D.Umar, A.Barrett, J. C.Nutrition and cancer prevention: a multidisciplinary perspective on human trialsAnnu Rev NutrAnnu Rev Nutr223-54242004(2, 3). It is not, however, so obvious that animal chemoprevention studies are useful  ADDIN EN.CITE Pound200437423742374217Pound, PandoraEbrahim, ShahSandercock, PeterBracken, Michael BRoberts, IanWhere is the evidence that animal research benefits humans?British Medical JournalBritish Medical Journal514-51732874382004(4). Major differences between rodents and humans in lifespan, body weight, intestinal morphology (e.g., caecum), gut microflora, way of eating (e.g., meals, chewing, coprophagia), and gene regulation may change the outcome of dietary interventions. Also, the profound differences in efficacy seen, even in different studies using one model, cast doubt on their relevance for clinical studies  ADDIN EN.CITE Gescher200356435643564317Gescher, A. J.Steward, W. P.Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrumCancer Epidemiol Biomarkers PrevCancer Epidemiol Biomarkers Prev953-712102003(5). The question thus needs to be scrutinized.

How good are rodent models of carcinogenesis in predicting chemopreventive efficacy in humans? From a theoretical viewpoint, how similar, or dissimilar, are rodent and human tumours? From an empirical viewpoint, are the chemopreventive effects of agents tested in rodents and humans consistent or discrepant? This review focuses on colorectal cancer prevention only, and goes through four steps: (i) Comparison of the mechanisms of colon carcinogenesis in humans and in animal models. (ii) Review of human intervention studies aimed at preventing colorectal tumours. (iii) Meta-analysis of animal intervention studies  ADDIN EN.CITE Pound200437423742374217Pound, PandoraEbrahim, ShahSandercock, PeterBracken, Michael BRoberts, IanWhere is the evidence that animal research benefits humans?British Medical JournalBritish Medical Journal514-51732874382004(4). The meta-analysis was restricted to aspirin, beta-carotene, calcium and wheat bran, the only agents tested in several human trials. (iv) The efficacy of chemopreventive agents in animals and in humans was then compared.

2. Comparison of the mechanisms of colon carcinogenesis in humans and in animal models

Let us look first at colon carcinogenesis in humans, then in rodent models. Vogelstein model relates the histological progression from normal tissue to cancer with the sequential accumulation of mutations  ADDIN EN.CITE Kinzler199624582458245817Kinzler, K.W.Vogelstein, B.Lessons from hereditary colorectal cancerCellCell159-170872PCC199619963240Vogelstein200049864986498617Vogelstein, B.Lane, D.Levine, A.J.Surfing the p53 networkNatureNature307-310408PCC200020006499(6, 7). Most human adenocarcinoma would evolve from aberrant crypt foci (ACF) and adenoma. This model has been progressively enriched, and several interdependent pathways are now accepted, based on the analysis of sporadic tumours and of two inherited syndromes: the familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancers (HNPCC). Germline mutation of the Apc gene determines the FAP syndrome. Most colorectal cancers are sporadic (90%), but they share with FAP tumours the same early Apc mutation in 50 to 80% of cases. In most sporadic colon cancers, like in FAP, a consequence of Apc gene mutation is b-catenin accumulation. Indeed APC protein forms a complex with b-catenin, axin, and glycogen synthase-3² kinase (GSK3²). Axin promotes ²-catenin phosphorylation that mediates its degradation in the proteasome  ADDIN EN.CITE Xing200357245724572417Xing, Y.Clements, W.K.Kimelman, D.Xu, W.Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex.Genes DevelopmentGenes Development2753-27641722beta Catenin2003(8). In normal cell, this is regulated by the Wingless/Wnt signaling pathway. But Apc mutation prevents the formation of the complex, and b-catenin level rises in the cytoplasm. The stabilized ²-catenin associates with transcription factor Tcf4. b-catenin-Tcf4 translocates into the nucleus, and induces constitutive activation of c-myc, cyclin D1 and c-jun  ADDIN EN.CITE Clevers200457255725572517Clevers, H.Wnt breakers in colon cancer.Cancer CellCancer Cell5-651beta Catenin2004(9). The disruption of the Wnt/b-catenin/Tcf pathway is thus a major event in most colon cancers. Chromosomal instability (CIN), a common feature of 8/10 colorectal cancers  ADDIN EN.CITE Fodde200157265726572617Fodde, R.Kuipers, J.Rosenberg, C.Smits, R.Kielman, M.Gaspar, C. Van Es, JH.Breukel, C.Wiegant, J.Giles, RH.Clevers, H.Mutations in the APC tumour suppressor gene cause chromosomal instability.Nature Cell BiologyNature Cell Biology433-438342001(10), goes with Apc mutation. Truncated APC protein may loose its ability to connect chromosomes to microtubules. Defective chromosome segregation, and CIN, would thus result from mutated Apc. Furthermore, in the tumours where Apc is intact, the b-catenin gene is mutated, and stabilized ²-catenin translocates into the nucleus and triggers c-myc, cyclin D1 and c-jun. In the multiple steps process from normal cell to carcinoma, other genes are mutated or deleted. The oncogene K-ras is mutated in the early stage of colon carcinogenesis, while tumour suppressor genes (DCC and p53) are involved in later stages  ADDIN EN.CITE Narayan200357275727572717Narayan, S.Roy, D.Role of APC and DNA mismatch repair genes in the development of colorectal cancers.Molecular CancerMolecular Cancer1-15241APC MMR2003(11). The process is also associated with over-expression of iNOS and COX-2, with resulting increase in nitric oxide and prostaglandin E2 levels. HNPCC syndrome is not due to Apc mutation but to a mutation in a mismatch repair (MMR) gene: several MMR genes are implicated as first event (Mlh1, Msh2, Msh6, Pms1, Pms2). Mutation rate is 100–1000-fold greater in MMR-deficient cells than in normal cells. This is evidenced by microsatellite instability (MSI), which participates to the hypermutable phenotype  ADDIN EN.CITE Chung200357285728572817Chung, DC.Rustgi, AK.The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications.Ann Intern MedAnn Intern Med560-5701387HNPCC2003(12). Most microsatellites are found in noncoding DNA, but some mutations due to MSI modify genes involved in later stages of carcinogenesis, e.g., transforming growth factor-² receptor II and insulin like growth factor II receptor. Besides mutations, human tumours have a general DNA hypomethylation, but the aberrant hypermethylation of promoter CpG islands leads to transcriptional silencing of key growth-controlling genes and contributes to cancer progression  ADDIN EN.CITE Trinh200257295729572917Trinh, B.N.Long, T.I.Nickel, AE.Shibata, D.Laird, P.W.DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair.Molecular and Cellular BiologyMolecular and Cellular Biology2906-2917229Mlh1DNA methylation2002(13).

Do tumours in animal models, i.e. carcinogen-initiated rats and mutated mice, share the genetic events and the histological features of human cancers? The use of carcinogens has been necessary because laboratory rodents have extremely low spontaneous rates of colon cancer. Most published studies were done in rats injected with dimethylhydrazine (DMH) or its metabolite, azoxymethane (AOM). AOM-induced tumours in rats share many histopathologic characteristics with human tumours, and similarly go through ACF, adenoma (often polyps) and carcinoma. They, like human tumours, often bear K-ras mutation (30-60%), but, unlike human tumours, they seldom have a mutated Apc (8%), and never a p53 mutation. However, like Apc mutated human tumours, rat tumours accumulate b-catenin in the nucleus. This is due to Ctnnb1 mutation, which produces a b-catenin resistant to degradation  ADDIN EN.CITE Femia20055730573017Femia, A.P.Bendinelli, B.Giannini, A.Salvadori, M. Pinzani, P. Dolara, P.Caderni, G.Mucin-depleted foci have beta-catenin gene mutations, altered expression of its protein, and are dose- and time-dependent in the colon of 1,2-dimethylhydrazine-treated rats.International Journal of Cancerin the press2005(14). Alternatively, a mutation in the GSK3b phosphorylation motif of the b-catenin gene can reduce b-catenin degradation  ADDIN EN.CITE Takahashi200455525552555217Takahashi, M.Wakabayashi, K.Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodentsCancer ScienceCancer Science475-4809562004(15). Heterocyclic amines, e.g., 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are also used to induce tumours in rats or mice. PhIP induces Apc (15%) and bð-catenin mutations (50%) in the colon of rats  ADDIN EN.CITE Tsukamoto200048514851485117Tsukamoto, T.Tanaka, H.Fukami, H.Inoue, M.Takahashi, M.Wakabayashi, K.Tatematsu, M.More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (phIP)-treated ratsJapanese Journal of Cancer ResearchJapanese Journal of Cancer Research792-796918PCC200020006300(16). The direct acting nitrosamine methylnitrosourea (MNU) has been used in few studies. In contrast with DMH-, AOM- and PhIP-induced tumours, no Apc or b-catenin mutations were detected in MNU-induced tumours. Thus, Wnt/bð-catenin/Tcf pathway plays a major role in human tumours and in carcinogen-induced rat tumours. Like in humans, COX-2 and iNOS are over-expressed in these tumours. However, these rodent carcinogens are not found in human diet (except PhIP), and use of large doses of a carcinogen is not comparable to the human situation. Although the carcinogen-induced tumours look similar to human tumours, we do not really know if they develop like spontaneous tumours. Perhaps the protection (or the promotion) depends on the tumour initiator.

A mutant mouse, Min, was found with multiple intestinal neoplasia in 1990  ADDIN EN.CITE Moser199032563256325617Moser, A.R.Pitot, H.C.Dove, W.F.A dominant mutation that predisposes to multiple intestinal neoplasia in the mouseScienceScience322-324247PCC TAPOCI199019904334(17). It was shown to have a germline inactivation of one Apc gene, similar to that in patients with FAP, and in many sporadic cancers. This promising animal model mimics the rapid development of adenomatous polyps that affect FAP patients. The Apc protein deficiency in Min mice results from a premature translational stop codon at amino acid 850. Other mice have also been genetically modified on Apc with truncations in positions 580, 716, 1309, or 1638. Like in humans, different mutations lead to different phenotypes and Wnt/b-catenin/Tcf pathway plays an important role in mutant mice carcinogenesis. For instance, Min mice have ten times more polyps than Apc1638, but six times fewer than Apc716 mutant mice  ADDIN EN.CITE Corpet200395495495417Corpet, D.E.Pierre, F.Point: from animal models to prevention of colon cancer. systematic review of chemoprevention in min mice and choice of the model systemCancer Epidemiology Biomarkers & PreventionCancer Epidemiology Biomarkers & Prevention391-400125PCC200320031275(18). In addition, COX-2 and iNOS play an important role in Min mice carcinogenesis, like in humans: knockout Min mice with deleted COX-2 or iNOS gene(s) develop fewer adenomas than "wild-type" Min mice  ADDIN EN.CITE Ahn200131313117Ahn, B.Ohshima, H.Suppression of intestinal polyposis in Apc (Min/+) mice by inhibiting nitric oxide productionCancer ResearchCancer Research8357-83606123PCC2001200157Oshima199635163516351617Oshima, M.Dinchuk, J.E.Kargman, S.L.Oshima, H.Hancock, B.Kwong, E.Trzaskos, J.M.Evans, J.F.Taketo, M.M.Suppression of intestinal polyposis in apc(delta 716) knockout mice by inhibition of cyclooxygenase 2 (COX-2)CellCell803-809875PCC199619964643(19, 20). Like in humans, methylation plays a role in Min mice carcinogenesis, since a reduction in DNA methyltransferase activity suppresses polyp formation  ADDIN EN.CITE Laird199526142614261417Laird, P.W.Jackson-Grusby, L.Fazeli, A.Dickinson, S.L.Jung, W.E.Li, E.Weinberg, R.A. Jaenisch, R.Suppression of intestinal neoplasi by DNA hypomethylationCellCell197-205812PCC199519953445(21). K-ras and p53 mutations are not detected in Min mice tumours, in contrast with human tumours. Besides Apc mutant mice, mice with Msh2 or Mlh1 gene mutations were obtained, but their phenotype does not make them a clear model for HNPCC patients  ADDIN EN.CITE DeWind199811301130113017DeWind, N.Dekker, M.VanRossum, A.VanderValk, M.Riele, H.T.Mouse models for hereditary nonpolyposis colorectal cancerCancer ResearchCancer Research248-255582PCC199819981548(22). However, Msh2-deficient mice develop small intestinal tumours and sebaceous gland tumors analogous to Msh2-mutated patients (Muir–Torre syndrome). Like human HNPCC, Msh2-/- and Mlh1-/- mouse cells display high mutation frequencies and MSI  ADDIN EN.CITE Wei200251085108510817Wei, K.Kucherlapati, R.Edelmann, W.Mouse models for human DNA mismatch-repair gene defectsTrends in Molecular MedicineTrends in Molecular Medicine346-35387PCC200220026657(23).
Table 1: Experimental colon tumour prevention in Man. Randomized double-blinded placebo-controlled published intervention studies are ranked by potency to prevent polyp recurrence, and grouped by agent.

Agent or DietReference Relative Risk (95% confidence interval)No. of treated patientsLength, monthsDaily doseColon endpointPrimary endpointSeleniumClark 960.42 (0.18-0.95) 65354200 µgCancer incid.Skin cancervitC,vitE,Bcar,Se,ZnHercberg 040.71 (0.39-1.31)252090176 mgCancer incid.All cancersCelecoxibSteinbach 000.72 polyp/patient30FAP 6800 mgPolyp no.SulindacGiardiello 020.78 (0.4-1.5)21FAP48300 mgPolyp no.CalciumBaron 990.85 (0.74-0.98)464181.2 gPolyp recur.CalciumBonithon 000.66 (0.38-1.17)176362 gPolyp recur.Calcium +vit. MixHofstad 980.71 (0.5-1.0)42361.6 gPolyp recur.Polyp growthAspirinBaron 030.81 (0.69-0.96)3773381 mgPolyp recur.AspirinBaron 030.96 (0.81-1.13)37233325 mgPolyp recur.AspirinBenamouzig 030.61 (0.37-0.99)6012300 mgPolyp recur.AspirinBenamouzig 030.85 (0.57-1.26)6612160 mgPolyp recur.AspirinGann 930.86 (0.68-1.10)1103560162 mgPolyp incid.Heart attackAspirinSandler 030.65 (0.46-0.91)31731325 mgPolyp recur.Ursodeoxycholic acidAlberts 050.88 (0.73-1.05)6613275 0 mgPolyp recur.Wheat branAlberts 000.88 (0.7-1.1)71935+11 gPolyp recur.Wheat branMacLennan 951.2 (0.8-2.0)15048+25 gPolyp recur.Wheat branMcKeown 941.2 (0.6-2.2)9924+15 gPolyp recur.Low fat MacLennan 950.9 (0.6-1.5)15148-7%Polyp recur.Low fat McKeown 941.2 (0.6-2.2)9924-9%Polyp recur.Low fat Schatzkin 001.00 (0.90-1.12)95836-10%Polyp recur.Beta-caroteneGreenberg 941.01 (0.85-1.20)3594825 mgPolyp recur.Beta-caroteneMacLennan 951.5 (0.9-2.5)1564820 mgPolyp recur.Beta-caroteneHennekens 961 NS1103514425 mgAll cancersHeart attackBeta-caroteneMalila 990.98 (0.71-1.35)77617820 mgPolyp incid.Lung cancerFruits & vegetablesSchatzkin 001.00 (0.90-1.12)95836+2servPolyp recur.Vit. C + vit. EGreenberg 941.08 (0.91-1.29)380481+0.4 gPolyp recur.Vit. C + vit. EMcKeown 880.86 (0.51-1.45)70240.4+0.4 gPolyp recur.Vit. EMalila 991.66 (1.19-2.32)77687850 mgPolyp incid.Lung cancerPsyllium Bonithon 001.67 (1.01-2.76)198363.5 gPolyp recur. 
The (Apc(+/-)) mice are promising models of human colorectal cancer  ADDIN EN.CITE Green20055750575017Green, J. E.Hudson, T.The promise of genetically engineered mice for cancer prevention studiesNat Rev Cancer184-98532005(24). However, a major drawback is that the tumours occur predominantly in the small intestine, not the colon. In addition, ACF and adenocarcinomas are not or seldom observed in this model. However, two new mutant mice may avoid these drawbacks. Germline targeted deletion of Apc exon 14 leads to severe colon polyposis: 5-15 polyps develop in these mice colo-rectum, vs. 0.4-4 in other Apc mutants  ADDIN EN.CITE Colnot200456795679567917Colnot, S.Niwa-Kawakita, M.Hamard, G.Godard, C.Le Plenier, S.Houbron, C.Romagnolo, B.Berrebi, D.Giovannini, M.Perret, C.Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiersLab InvestLab Invest1619-3084122004(25). Other mice, with a N-terminal truncated bð-catenin (A33DðNbðcat), develop few spontaneous ACF in the colon, like human and rat models  ADDIN EN.CITE Orner200235083508350817Orner, G.A.Dashwood, W.M.Blum, C.A.Diaz, G.D.Li, Q.J.Alfageeh, M.Tebbutt, N.Heath, J.K.Ernst, M.Dashwood, R.H.Response of Apc(min) and A33(delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (phIP)Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis121-127506Sp. Iss.PCC200220024634(26).

Taken together, rodent models grow tumours that share many histological and genetic features with humans. The major differences between rodents and humans are the small bowel location of tumours in Min mice (vs. human colon), and the mutation of beta-catenin gene in AOM-injected rats (vs. human Apc mutations). These conclusions render it pertinent to examine studies of intestinal tumour chemoprevention in humans, and to compare them with results obtained in rodent models.


3. Experimental chemoprevention of intestinal tumours in humans

Randomized, placebo-controlled trials directed at preventing the recurrence of colonic adenomatous polyps in human volunteers are considered the gold standard for chemoprevention studies though they do have limitations. The major one is that the study end-point is not cancer incidence but adenoma recurrence. Other limitations are the short length of the intervention compared with the duration of the disease, the possible lack of compliance with the protocol, and the inclusion of subjects that differ from the general population  ADDIN EN.CITE Forman200457345734573417Forman, M. R.Hursting, S. D.Umar, A.Barrett, J. C.Nutrition and cancer prevention: a multidisciplinary perspective on human trialsAnnu Rev NutrAnnu Rev Nutr223-54242004(3). Two agents, calcium  ADDIN EN.CITE  ADDIN EN.CITE.DATA (27-29) and aspirin  ADDIN EN.CITE  ADDIN EN.CITE.DATA (30-32), consistently reduced polyp recurrence in several intervention studies (Table 1). The estimated "weighted mean RRs" for calcium and aspirin were 0.79 and 0.85 respectively (weighted by study size). A recently published meta-analysis finds an RR= 0.80 (CI: 0.68, 0.93) for calcium supplement  ADDIN EN.CITE Shaukat200557055705570517Shaukat, A.Scouras, N.Schunemann, H. J.Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trialsAm J GastroenterolAm J Gastroenterol390-410022005Feb15667497(33), which is close to the value estimated here, 0.79. Interventions with high wheat bran and/or low fat diet, beta-carotene or vitamin C and E had no effect at all on polyp recurrence  ADDIN EN.CITE  ADDIN EN.CITE.DATA (34-39). The "weighted Table 2: Meta-analysis of chemoprevention studies in carcinogen-initiated rats, dealing with aspirin, beta-carotene, calcium and wheat bran protection. Relative risks (RRs) calculated with Random Model, except underlined values, calculated by Chi-square test on 2x2 tables. Data subsets shown in italics (full data and figures on http://corpet.net/min)

Treatment2x2 Table : No. of RatsRR95% C.I.p ValueWith tumour TotalAspirin treated rats3135590.840.75-0.950.006No aspirin controls1672520.860.77-0.960.007Aspirin during initiation only0.680.42-1.160.13Aspirin "both" periods0.800.67-0.950.012Aspirin post-initiation only0.920.79-1.080.32Beta-carotene treated rats54950.760.61-0.930.005No beta-carotene controls821090.720.47-1.080.11High calcium treated rats5489840.910.84-0.990.03Low calcium controls4567480.920.85-1.000.06Calcium in High Fat diets0.930.86-1.020.11Calcium in Low Fat diets0.920.77-1.110.38Calcium lactate0.720.55-0.940.02Ca phosph., carbon., gluconate0.990.95-1.040.74Wheat bran treated rats3075950.830.75-0.910.0002No wheat bran controls3555690.870.77-0.970.015Wheat bran in High Fat diets0.790.66-0.930.006Wheat bran in Low Fat diets0.910.78-1.070.26 mean RRs" were estimated to be 0.96, 1.00, 1.00 and 1.04 respectively. Table 1 shows the effect of other interventions: mixtures, complex dietary changes, or once only tested agents. We chose to focus this meta-analysis on agents fulfilling two criteria: (i) well-defined agent, (ii) several concordant human trials. Accordingly, aspirin, beta-carotene, calcium, and wheat bran effect in rodents were further examined.

4. Chemoprevention in animal models of intestinal carcinogenesis.

According to the provocative article by Pound et al.  ADDIN EN.CITE Pound200437423742374217Pound, PandoraEbrahim, ShahSandercock, PeterBracken, Michael BRoberts, IanWhere is the evidence that animal research benefits humans?British Medical JournalBritish Medical Journal514-51732874382004(4), systematic reviews should become routine to ensure the best use of existing animal data, and improve the estimates of effect from animal experiments. We thus made a systematic review of aspirin, beta-carotene, calcium, and wheat bran dietary chemoprevention studies in two animal models of colorectal cancer: carcinogen-initiated rats (and mice), and mice mutated on the Apc gene (Min mice mainly).

4.1. Methods.

The meta-analysis of carcinogen-injected rats was done as follows: we searched articles on Medline/PubMed database and in "references" sections (cut-off date, January 2005). Some papers were not included: not in English, poor protocol, missing or aberrant data (list given on http://corpet.net/min). Studies were far from homogeneity (all Q Cochran's p¸kd>$$If”ÿÖ´ñÿÁJ
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