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Doi:10.1016/j.ejca.2005.06.006EuropeanJournal ofCancer European Journal of Cancer xxx (2005) xxx–xxx 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 UMR Xenobiotiques, Institut National Recherche Agronomique, Ecole Nationale Veterinaire Toulouse, BP-87614, 23 Capelles, 31076 Toulouse, France Received 31 March 2005; received in revised form 13 June 2005; accepted 15 June 2005 Tumours in rodent and human colon share many histological and genetic features. To know if rodent models of colon carcino- genesis are good predictors of chemopreventive eﬃcacy in humans, we conducted a meta-analysis of aspirin, b-carotene, calcium,and wheat bran studies. Controlled intervention studies of adenoma recurrence in human volunteers were compared with chemo-prevention studies of carcinogen-induced tumours in rats, and of polyps in Min (Apc(+/ )) mice: 6714 volunteers, 3911 rats and 458mice were included in the meta-analyses. Diﬀerence between models was small since most global relative risks were between 0.76 and1.00. A closer look showed that carcinogen-induced rat studies matched human trials for aspirin, calcium, carotene, and were com-patible 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 accuratefor 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 andchemoprevention.
2005 Elsevier Ltd. All rights reserved.
Keywords: Animal model; Diet; Chemoprevention; Colon-carcinogenesis; Min mice; Chemically-induced; Aspirin; b-carotene; Calcium; Wheatbran; Meta-analysis; Systematic review biological functions, and rodents are valuable for toxic-ity tests. Rodent studies are needed in the chemopreven- Some 100,000 rodents have been sacriﬁced on the tion area, because epidemiological studies do not lead to chemoprevention altar. This number was estimated ﬁrm conclusions as confusing factors cannot be fully from the colon cancer chemoprevention database eliminated. Thus, the hypotheses generated by epidemi- (). The estimate includes liver, ology must be tested in controlled experiments, ideally mammary, oesophagus, pancreas prostate, and skin can- in humans But this is very long and costly, and it cer studies. Were these sacriﬁces useful? Were the time, could jeopardise volunteersÕ health. Thus, animal trials eﬀorts, and money needed to raise rodents, and to try should precede human trials. For instance, animal stud- to prevent their tumours of any use? The answer may ies should have been completed before b-carotene seem obvious, since rodents and humans share many administration to smokers It is not, however, soobvious that animal chemoprevention studies are usefulMajor diﬀerences between rodents and humans in * Corresponding author. Tel.: +33 561 193 982; fax: +33 561 491 lifespan, body weight, intestinal morphology (e.g. cae- E-mail address: (D.E. Corpet).
cum), gut microﬂora, way of eating (e.g. meals, chewing, 0959-8049/$ - see front matter 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejca.2005.06.006 D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx coprophagia), and gene regulation may change the out- cers is associated with Apc mutations. Truncated come of dietary interventions. Also, the profound diﬀer- APC protein may loose its ability to connect chromo- ences in eﬃcacy seen, even in diﬀerent studies using one somes to microtubules. Defective chromosome segrega- model, cast doubt on their relevance for clinical studies tion, and CIN, would thus result from mutated Apc.
The question thus needs to be scrutinised.
Furthermore, in the tumours where Apc is intact, the How good are rodent models of carcinogenesis in b-catenin gene is mutated, and stabilised b-catenin trans- predicting chemopreventive eﬃcacy in humans? From locates into the nucleus and triggers c-myc, cyclin D1 a theoretical viewpoint, how similar, or dissimilar, are and c-jun. In the multiple step process from normal cell rodent and human tumours? From an empirical view- to carcinoma, other genes are mutated or deleted. The point, are the chemopreventive eﬀects of agents tested oncogene K-ras is mutated in the early stage of colon in rodents and humans consistent or not? This review fo- carcinogenesis, while tumour suppressor genes (DCC cuses on colorectal cancer prevention only, and goes and p53) are involved in later stages . The process through four steps: (a) comparison of the mechanisms is also associated with over-expression of iNOS and of colon carcinogenesis in humans and in animal mod- COX-2, with resulting increase in nitric oxide and pros- els; (b) review of human intervention studies aimed at taglandin E2 levels. HNPCC syndrome is not due to Apc preventing colorectal tumours; (c) meta-analysis of ani- mutations but to a mutation in a mismatch repair mal intervention studies . The meta-analysis was re- (MMR) gene: several MMR genes are implicated in ﬁrst stricted to aspirin, b-carotene, calcium and wheat event (Mlh1, Msh2, Msh6, Pms1, Pms2). Mutation rate bran, the only agents tested in several human trials; is 100–1000-fold greater in MMR-deﬁcient cells than in and (d) the eﬃcacy of chemopreventive agents in ani- normal cells. This is evidenced by microsatellite instabil- mals and in humans was then compared.
ity (MSI), which participates to the hypermutable phe-notype noncoding DNA, but some mutations due to MSI mod- 2. Comparison of the mechanisms of colon carcinogenesis ify genes involved in later stages of carcinogenesis, e.g.
in humans and in animal models transforming growth factor-b receptor II and insulinlike growth factor II receptor. Besides mutations, hu- Let us look ﬁrst at colon carcinogenesis in humans, man tumours have a general DNA hypomethylation sta- then in rodent models. Vogelstein model relates the his- tus, and the aberrant hypermethylation of promoter tological progression from normal tissue to cancer with CpG islands leads to transcriptional silencing of key the sequential accumulation of mutations . Most growth-controlling genes and contributes to cancer pro- human adenocarcinoma would evolve from aberrant crypt foci (ACF) and adenoma. This model has been Do tumours in animal models, i.e. carcinogen-initi- progressively enriched, and several interdependent path- ated rats and mutated mice, share the genetic events ways are now accepted, based on the analysis of spo- and the histological features of human cancers? The radic tumours and of two inherited syndromes: the use of carcinogens has been necessary because labora- familial adenomatous polyposis (FAP) and hereditary tory rodents have extremely low spontaneous rates of nonpolyposis colorectal cancers (HNPCC). Germline colon cancer. Most published studies were done in rats mutation of the Apc gene determines the FAP syn- injected with dimethylhydrazine (DMH) or its metabo- drome. Most colorectal cancers are sporadic (90%), lite, azoxymethane (AOM). AOM-induced tumours in but they share with FAP tumours the same early Apc rats share many histopathologic characteristics with hu- mutation in 50–80% of cases. In most sporadic colon man tumours, and similarly go through ACF, adenoma cancers, like in FAP, a consequence of Apc gene muta- (often polyps) and carcinoma. They, like human tu- tion is b-catenin accumulation. Indeed APC protein mours, often bear K-ras mutation (30–60%), but, unlike forms a complex with b-catenin, axin, and glycogen syn- human tumours, they seldom have a mutated Apc (8%), thase-3b kinase (GSK3b). Axin promotes b-catenin and never a p53 mutation. However, like Apc mutated phosphorylation that mediates its degradation in the human tumours, rat tumours accumulate b-catenin in proteasome . In normal cells, this process is regulated the nucleus. This is due to Ctnnb1 mutation, which pro- by the Wingless/Wnt signaling pathway, but mutations duces a b-catenin resistant to degradation Alterna- in Apc prevents the formation of the complex, and b- tively, a mutation in the GSK3b phosphorylation motif catenin level rises in the cytoplasm. The stabilised b- of the b-catenin gene can reduce b-catenin degradation catenin associates with transcription factor Tcf4. b-cate- Heterocyclic amines, e.g. 2-amino-1-methyl-6- nin-Tcf4 translocates into the nucleus, and induces con- phenylimidazo[4,5-b]pyridine (PhIP), are also used to in- stitutive activation of c-myc, cyclin D1 and c-jun The duce tumours in rats or mice. PhIP induces Apc (15%) disruption of the Wnt/b-catenin/Tcf pathway is thus a and b-catenin mutations (50%) in the colon of rats major event in most colon cancers. Chromosomal insta- The direct acting nitrosamine methylnitrosourea bility (CIN), a common feature of 8/10 colorectal can- (MNU) has been used in few studies. In contrast with D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx DMH-, AOM- and PhIP-induced tumours, no Apc or b- develop few spontaneous ACF in the colon, like human catenin mutations were detected in MNU-induced tu- mours. Thus, Wnt/b-catenin/Tcf pathway plays a major Taken together, rodent models grow tumours that role in human tumours and in carcinogen-induced rat share many histological and genetic features with hu- tumours. Like in humans, COX-2 and iNOS are over- mans. The major diﬀerences between rodents and hu- expressed in these tumours. However, these rodent car- mans are the small bowel location of tumours in Min cinogens are not found in human diet (except PhIP), and mice (vs. human colon), and the mutation of b-catenin use of large doses of a carcinogen is not comparable to gene in AOM-injected rats (vs. human Apc mutations).
the human situation. Although the carcinogen-induced These conclusions render it pertinent to examine studies tumours look similar to human tumours, we do not of intestinal tumour chemoprevention in humans, and to really know if they develop like spontaneous tumours.
compare them with results obtained in rodent models.
Perhaps the protection (or the promotion) depends onthe tumour initiator.
The mutant mouse, Min, was found with multiple 3. Experimental chemoprevention of intestinal tumours in intestinal neoplasia in 1990 . It was shown to have a germline inactivation of one Apc gene, similar to thatin patients with FAP, and in many sporadic cancers.
Randomised, placebo-controlled trials directed at This promising animal model mimics the rapid devel- preventing the recurrence of colonic adenomatous pol- opment of adenomatous polyps that aﬀect FAP pa- yps in human volunteers are considered the gold stan- tients. The Apc protein deﬁciency in Min mice results dard for chemoprevention studies though they do from a premature translational stop codon at amino have limitations. The major one is that the study acid 850. Other mice have also been genetically modi- end-point is not cancer incidence but adenoma recur- ﬁed on Apc with truncations in positions 580, 716, rence. Other limitations are the short length of the 1309, or 1638. Like in humans, diﬀerent mutations lead intervention compared with the duration of the dis- to diﬀerent phenotypes and Wnt/b-catenin/Tcf path- ease, the possible lack of compliance with the proto- way plays an important role in mutant mice carcino- col, and the inclusion of subjects that diﬀer from the genesis. For instance, Min mice have ten times more general population Two agents, calcium polyps than Apc 1638, but six times fewer than Apc and aspirin , consistently reduced polyp recur- 716 mutant mice In addition, COX-2 and iNOS rence in several intervention studies The play an important role in Min mice carcinogenesis, like estimated ‘‘weighted mean RRs'' for calcium and aspi- in humans: knockout Min mice with deleted COX-2 or rin were 0.79 and 0.85, respectively (weighted by study iNOS gene(s) develop fewer adenomas than ‘‘wild- size). A recently published meta-analysis ﬁnds an type'' Min mice Like in humans, methylation RR = 0.80 (CI: 0.68, 0.93) for calcium supplement plays a role in Min mice carcinogenesis, since a reduc- which is close to the value estimated here, 0.79.
tion in DNA methyltransferase activity suppresses Interventions with high wheat bran and/or low fat polyp formation K-ras and p53 mutations are diet, b-carotene or vitamin C and E had no eﬀect at not detected in Min mice tumours, in contrast with hu- all on polyp recurrence The ‘‘weighted mean man tumours. Besides Apc mutant mice, mice with RRs'' were estimated to be 0.96, 1.00, 1.00 and 1.04, Msh2 or Mlh1 gene mutations were obtained, but their respectively. shows the eﬀect of other inter- phenotype does not make them a clear model for ventions: mixtures, complex dietary changes, or once HNPCC patients However, Msh2-deﬁcient mice only tested agents. We chose to focus this meta-anal- develop small intestinal tumours and sebaceous gland ysis on agents fulﬁlling two criteria: (a) well-deﬁned tumors analogous to Msh2-mutated patients (Muir– agent, (b) several concordant human trials. Accord- Torre syndrome). Like human HNPCC, Msh2 / ingly, aspirin, b-carotene, calcium, and wheat bran ef- mouse cells display high mutation fre- fect in rodents were further examined.
quencies and MSI The (Apc(+/ )) mice are promising models of human colorectal cancer . However, a major drawback is 4. Chemoprevention in animal models of intestinal that the tumours occur predominantly in the small intes- tine, not the colon. In addition, ACF and adenocarcino-mas are not or seldom observed in this model. However, According to the provocative article by Pound et al.
two new mutant mice may avoid these drawbacks.
systematic reviews should become routine to ensure Germline targeted deletion of Apc exon 14 leads to se- the best use of existing animal data, and improve the vere colon polyposis: 5–15 polyps develop in these mice estimates of eﬀect from animal experiments. We thus colo-rectum, vs. 0.4–4 in other Apc mutants Other made a systematic review of aspirin, b-carotene, cal- mice, with a N-terminal truncated b-catenin (A33DNbcat), cium, and wheat bran dietary chemoprevention studies D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx Table 1Experimental colon tumour prevention in man ﬁdence interval) 0.42 (0.18–0.95) Cancer incid.
vitC, vitE, Bcar, Se, Zn 0.71 (0.39–1.31) Cancer incid.
0.72 polyp/patient 0.85 (0.74–0.98) Polyp recur.
0.66 (0.38–1.17) Polyp recur.
Calcium + vit. Mix Polyp recur.
0.81 (0.69–0.96) Polyp recur.
0.96 (0.81–1.13) Polyp recur.
0.61 (0.37–0.99) Polyp recur.
0.85 (0.57–1.26) Polyp recur.
0.86 (0.68–1.10) Polyp incid.
0.65 (0.46–0.91) Polyp recur.
Ursodeoxycholic acid 0.88 (0.73–1.05) Polyp recur.
1.00 (0.90–1.12) Polyp recur.
1.01 (0.85–1.20) Polyp recur.
0.98 (0.71–1.35) Polyp incid.
Fruits and vegetables 1.00 (0.90–1.12) Polyp recur.
1.08 (0.91–1.29) Polyp recur.
0.86 (0.51–1.45) Polyp recur.
1.66 (1.19–2.32) Polyp incid.
1.67 (1.01–2.76) Polyp recur.
Randomised double-blinded placebo-controlled published intervention studies are ranked by potency to prevent polyp recurrence, and grouped byagent.
in two animal models of colorectal cancer: carcinogen- duplicate some control data, because many studies use initiated rats (and mice), and mice mutated on the Apc a single control group for several treated groups. Each gene (Min mice mainly).
control rat was thus included several times in the table,which should not be. We thus added a second approach, by pooling data. This is not recommended as a rule be-cause it gives too little weight to studies with low base- The meta-analysis of carcinogen-injected rats was line levels of adenomas. Raw numbers of tumour- done as follows: we searched articles on Medline/Pub- bearing rats, and of tumour-free rats, in control and Med database and in ‘‘references'' sections (cut-oﬀ date, treated groups, were included in a table, and summed January 2005). Some papers were not included: those up as if all rats had been treated in a single study (each not in English, poor protocol design, missing or aber- control rat was included only once). The 2 · 2 contin- rant data (list given on Studies gency table with all rats (shown on was then were far from homogeneity (all Q CochranÕs P < 0.01), analysed with v2 statistics without Yates correction, which disqualiﬁed ‘‘Fixed Eﬀects'' model ‘‘Random and 95%CI were calculated and shown in . Pool- Eﬀects'' model was used to calculate common RR, 95% ing of data from all studies was chosen, including rats conﬁdence intervals (95%CI) and P values which and mice, initiated by various carcinogens, and treated are shown in Funnel plots were drawn to detect with various doses. We reasoned that when a human publication bias, which were tested by rank test population is treated with a chemopreventive agent, However, the random model calculation needed to people are exposed to various carcinogens, and have dif- D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx Table 2Meta-analysis of chemoprevention studies in carcinogen-initiated rats, dealing with aspirin, beta-carotene, calcium and wheat bran protection 2 × 2 table: no. of rats Aspirin treated rats No aspirin controls Aspirin during initiation only Aspirin ‘‘both'' periods Aspirin post-initiation only β- carotene treated rats No beta-carotene controls High calcium treated rats Low calcium controls Calcium in high fat diets Calcium in low fat diets Calcium lactate Ca phosph., carbon., gluconate Wheat bran treated rats No wheat bran controls Wheat bran in high fat diets Wheat bran in low fat diets Relative risks (RRs) calculated with random model, except underlined values, calculated by v2 test on 2 · 2 tables. Data subsets shown in italics (fulldata and ﬁgures on ).
ferent genetic backgrounds and diﬀerent diets. We thus had no a priori reason to exclude any rodent protocol.
The meta-analysis of Min mice intestinal polyp stud- ies was done as follows: global eﬀect size and P value were ﬁrst calculated with ‘‘Random eﬀects'' modeland given in Section 4.2. However, a second ap-proach was also used, because ‘‘Eﬀect size'' can not be compared with RR. We thus chose to use ratios insteadof diﬀerences. Number of adenomas per mouse in trea- ted group was divided by corresponding value in controlgroup and multiplied by 100, for each study. The meanof these percentages was compared with the hypothetical Polyps /sml intest. Treated % Control
100% value (H0 hypothesis) in a one sample Student t Aspirin Calcium Wheat Bran
test. Also, a weighted mean was calculated, taking in to account the number of mice per study. Full rats and mice data and ﬁgures are shown on websiteand data are summarised here in(rats) and (Min mice).
4.2.1. Aspirin eﬀect in carcinogen-injected rats The meta-analysis of eight publications including 811 rats showed that aspirin reduces colon Polyps /colon, Treated % Control
tumour incidence in rats: RR = 0.84 (P = 0.006), with Aspirin Calcium Wheat Bran
similar RR with Random model analysis (0.86, P = 0.007). Analysis of subsets where aspirin was gi- Fig. 1. Eﬀect of interventions on number of tumours in Apc mutatedmice, expressed as percent of control (full data on ven only before or after the initiation is compatible (A) small intestine and (B) large intestine. Open circles: pre-birth with the hypothesis that the protection is higher when administration (aspirin), or ‘‘Western diet'' (data not included into aspirin treatment is given during initiation ( D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx 4.2.2. Aspirin eﬀect in mutated mice similar RR with random model (0.92, P = 0.06). The Seven articles including 232 mice with an Apc muta- hypothesis that calcium can speciﬁcally reduce high-fat tion provide data on aspirin . Number of intesti- diet promotion was tested by analysing separately the nal adenomas in treated mice was 94% of number in studies with high-fat (>20% fat, w/w) and low-fat diets controls P = 0.59). Eﬀect size analysed by ran- (<6%). Both subsets yielded similar RRs and P values 0.29 (P = 0.03). This small reduction (). Also, we tested the hypothesis that some cal- of small intestinal polyps was thus signiﬁcant or not, cium salts were more protective than others. This was according to the model. Furthermore, aspirin treatment indeed the case: calcium lactate was protective in rats did not reduce the number of colonic polyps ((B)).
(RR = 0.7, P = 0.02, but phosphate, carbon- According to Perkins aspirin prevents the early ate and gluconate aﬀorded no protection (RR = 1).
phase of carcinogenesis, and would be active only beforebirth and until weaning. Data subsets were analysed to 4.2.5. Calcium eﬀect in mutated mice test this hypothesis. Mean numbers of polyps in the Small intestinal polyp yield increases by +9% and two early-treated groups of mice were 74 and 80% of +21% when dietary calcium is doubled 79 mice).
controls (, open circles), vs. 102% in mice only Calcium did not reduce the number of colonic polyps treated after weaning. This is compatible with the either (In contrast, mice fed the high-calcium hypothesis or early protection.
AIN76 diet had fewer polyps than mice fed the low-cal-cium Western diet designed by Newmark This 4.2.3. b-carotene eﬀect in carcinogen-injected rodents polyp reduction to 37% of control value (weighted The meta-analysis of four studies including mean, P < 0.001) cannot however be attributed to cal- 204 rats and mice showed that b-carotene reduces colon cium alone, since diets also diﬀered for phosphate, fat, tumour incidence in rodents: RR = 0.76 (P = 0.005).
and vitamin D content (, open circles).
However, this RR was not signiﬁcant using randommodel analysis (0.72, P = 0.11, No study of 4.2.6. Wheat bran eﬀects in carcinogen-injected rats b-carotene in Min mice was found.
A signiﬁcant protection by wheat bran is shown in two out of 12 publications Meta-analysis, 4.2.4. Calcium eﬀect in carcinogen-injected rats including 1164 rats, showed that wheat bran reduces co- The meta-analysis of 17 publications lon tumour incidence in rats (RR = 0.83, P = 0.0002), including 1732 rats showed that calcium reduces colon with similar RR in random model analysis (0.87, tumour incidence in rats: RR = 0.91 (P = 0.03), with P = 0.015). The hypothesis that wheat bran speciﬁcally Table 3Summary of dietary prevention of colorectal tumours in rats, mice and humans: Eﬃcacy of agents to reduce polyp recurrence in humans, tumourincidence in rats, and polyp number in mice Carcinogen-initiated rats, colon tumour Min mice, polyp number (small bowel) 0.86 (0.77–0.96) 0.94 (0.73–1.15) 0.92 (0.85–1.00) 0.87 (0.77–0.97) 0.64 (0.54–0.84) Fruits and veg.
a Top-panel data come from this meta-analysis full data and ﬁgures on b Bottom-panel data (in italics) from no true meta-analysis approach.
c RR: relative risk of polyp recurrence (humans) or of colon tumour incidence (rats).
d S, signiﬁcant. NS, not signiﬁcant.
e Number of articles included in the meta-analysis.
f Small scale study of polyp number reduction in FAP patients.
g Not signiﬁcant by random model analysis, but signiﬁcant by v2 analysis (see ).
h OK: rodent data match human data; ±OK: no direct match but human RR within 95%CI; NO: rodent data diﬀer from human data.
i PR: polyp ratio, number of intestinal polyps in treated mice divided by number in control mice.
j Not signiﬁcant by StudentÕs t test, but signiﬁcant by random model analysis: eﬀect size = 0.29, 95%CI = 0.55; 0.03.
D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx prevents fat promotion was tested by analysing sepa- rately studies with high-fat and low-fat diets. Wheat bran indeed protected rats given a high-fat diet A- RAT vs. MAN
(RR = 0.79, P = 0.006), but not rats given a low-fat diet 4.2.7. Wheat bran eﬀect in mutated mice The eight studies gathering 147 Min mice RR in Rats
showed a protective eﬀect of wheat bran Number of small intestinal polyps in wheat bran-fed mice was 69% of control number (weighted mean, 66%, P = 0.001), and eﬀect size was Fruits & Veg.
model analysis (P < 0.001). Bran also marginally de- creased colonic tumours (P = 0.07, 5. Comparison of intestinal chemoprevention in humansand in animal models B- MOUSE vs. MAN
shows that aspirin, b-carotene, calcium, and wheat bran eﬀect in men, rats and mice led to RRs com-prised between 0.72 and 1.00 (and PRs between 0.64 and1.15): no promotion and no strong protection were ob- served (The eﬀects of four agents in three models RR in Mice
were thus similar. However, signiﬁcances and 95%CIs suggest that: (a) aspirin protected men and rats, Fruits& veg.
but not Min mice (but human RR was within mice PR 95%CI); (b) b-carotene did not protect rats or men (no published Min mice study); (c) calcium protected men and rats, although eﬀect in men was stronger than in rats.
In a single study, Min mice were not protected ; and (d) wheat bran protected mice and rats, but not men (but human RR was within rat 95%CI). Carcinogen-induced rat studies matched human trials for aspirin, calcium, Fig. 2. Chemoprevention in humans and rodents (data from carotene, and were compatible for wheat bran. Min mice Colon polyp recurrence RR in humans vs. tumour RR in chemically- results were compatible with human results for aspirin, induced rats (panel RAT vs. MAN), or vs. Polyp ratio in Apc mutated but discordant for calcium and wheat bran (no carotene mice (panel MOUSE vs. MAN). Black points: meta-analysis data.
study). However, the size of these discrepancies was Grey points: tentative values from . Italics: RR signiﬁcance small and may not be meaningful. Bottom of re- discordant in humans and rodents.
ports rodent data from a previous review These re-sults should be considered with caution, because the true meta-analysis approach was not undertaken in rodents,and because the eﬀect in humans relied on single studies This meta-analysis of experimental studies suggests (except low-fat). The eﬀect of most of the diets or agents that the eﬀects of aspirin, b-carotene, calcium, and was consistent across the various models except one wheat bran were not strikingly diﬀerent in humans, rats striking discrepancy: psyllium aﬀorded strong protection and mice (However, the hypothesis that chemo- in one rat study, and signiﬁcant promotion in one human preventive agents produce the same eﬀect in animals and study. However, the ﬁrst published study of psyllium in humans has hitherto not been tested. Robust analysis (not reported here) showed a strong promotion in would require solid data on more than four agents, and DMH-initiated rats . The previous review concluded with more contrasted RRs (e.g. below 0.5 and above there was a reasonable agreement between the results of 1.0). already suggests that selenium, celecoxib, the animal studies and the more limited clinical studies and sulindac eﬀect in rodents could match the eﬀect in The present meta-analysis somewhat challenges this volunteers. Rodent models thus roughly predict eﬀect conclusion, because the prediction is not accurate for all in humans. A closer look at shows that carcin- agents, and carcinogen-induced rats model seems better ogen-induced rat studies matched human trials for aspi- than Min mice model.
rin, calcium, carotene, and were compatible for wheat D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx bran. Min mice results were compatible with human re- mour prevention in humans, as advocated by Bruce sults for aspirin, but discordant for wheat bran and cal- This notion is a distinct possibility, because, like in hu- cium (single calcium article, and no carotene study).
mans, the addition of calcium (and vitamin D) to the also suggests discordances for psyllium in rats, diet reduced tumour incidence in mice and low-fat diet in mice. Thus the rodent models do Animal studies may ‘‘predict'' what happens in hu- not predict accurately the outcome of intervention stud- mans. Here are two examples from our laboratory.
ies in humans for all agents, and Min mice do not ap- The ﬁrst example is the serendipitous discovery that pear to be superior to carcinogen-induced rats. The polyethylene glycol (PEG) is a potent chemopreventive following four considerations may explain the apparent agent in rats Four years later, a population study discrepancies between rodents and humans: showed that humans taking PEG-based laxatives haveonly half the risk of developing colorectal adenoma (i) Some agents may not aﬀord the same protection in compared to nonusers Another example is beef rodents and in humans (e.g. wheat bran). This meat promotion of carcinogenesis in rats. According means that rodent models would not be reliable to epidemiological studies consumption of beef predictors to detect chemopreventive agents.
has been suggested to increase colon cancer risk in hu- (ii) Diﬀerences in study design could preclude any pre- mans. Tumour promotion by beef may be mediated by cise quantitative comparison between rodents and myoglobin haem iron, and is fully inhibited by a high humans. Notably, genetic, diet, environment and calcium diet These data prompted the authors to treatment are fully controlled in rodent studies, ask epidemiologists to re-evaluate cohort results. Such not in human trials.
evaluation showed that high calcium intake was associ- (iii) Publication bias could distort rodent results. Bias ated with a stronger protection in those eating high lev- is probably much higher for rodent than for els of red meat than in those eating less than 25 g red human studies. In contrast with human trials, null meat/day (A. Flood, unpublished observation).
or negative rodent studies are less likely to be pub- Well known agents such as aspirin might perhaps not lished than positive ones. This bends the mean of have been the best ones to be subjected to this analysis, rodent results toward protection. For instance, since they seem to aﬀord only modest protection in rats several scientists have indicated to the authors that and in volunteers. One may surmise that the most potent in their opinion, their manuscripts were declined agents discovered in animal studies might aﬀord consis- because the results contradicted a currently tent protection when tested in volunteers. Rodent mod- accepted dogma (e.g. calcium is protective). To illustrate this point, the funnel plot of aspirin data protease inhibitor, sphingomyelin, physical exercise, in rats showed a signiﬁcant publication bias (plot EGF-receptor-kinase inhibitor, (+)-catechin, resvera- shown on P = 0.0007). Cal- trol, ﬁsh oil, curcumin, caﬀeic acid phenetyl-ester and cium and wheat bran data show no clear evidence S-methyl–methane–thiosulfonate might well be eﬃca- for bias. However, to reduce publication bias, cious preventive agents that have not yet been tested there should be an ethical obligation to post all in humans However, the safety of giving a daily unpublished results on an internet archive.
pill to thousands of healthy people for many years needs (iv) Lastly, the meta-analysis itself might be inaccu- to be carefully evaluated prior to a trial in order to rate. We may have missed important studies, or avoid the negative results associated with b-carotene the pooling of studies with diﬀerent protocols and speciﬁc COX2 inhibitors was perhaps not a good choice. Because RRs were In conclusion, how useful are the animal models? Do close to 1.00, changing the calculation method we have to agree with the letter sent by R. Greek and J.
could change the signiﬁcance (see notes g and j Greek to the Brit. Med. J. on 5 February, 2001? (Full text in However, these choices were made a priori, and there was no intention to bias the con- ) ‘‘Animals can only be proven to be ''models‘‘ clusion, which indeed contradicts the authors empirically. That is to say, we must know what happens starting opinion.
in humans ﬁrst, then study animals to see if a particularanimal replicates the human condition. . But this is a Could the artiﬁcial use of a potent carcinogen, or of a catch-22. We can only know which animal mimics hu- germline mutation, be the cause of the poor predictivity mans after we know what happens in humans. But after of rodent models? In NewmarkÕs model, normal mice we know how humans respond there is no need to use ani- were fed a ‘‘Western diet'', which contains high fat mals. This gives us no new knowledge, is obviously not and phosphate, and low calcium, vitamin D, ﬁbres, folic predictive, and thus obviates the need for animals.'' acid and vitamin B12. Eighteen months later, spontane- Although one cannot disagree completely with the ous colon tumours were observed in ﬁve mice out of 12 underlying sentiment expressed in this letter and has to . Could this model be the ultimate one to predict tu- admit that the empirical approach is necessary, rodent D.E. Corpet, F. Pierre / European Journal of Cancer xxx (2005) xxx–xxx studies remain undoubtedly useful for the following We thank W. Robert Bruce, Agne s Robin, Meige and (i) To screen for potential chemopreventive agents, Armelle Corpet for helpful discussions, the reviewers for and to eliminate agents that have no eﬀect or pro- useful advice, and a number of colleagues for sending mote tumour growth. In , all the agents their ancient papers without delay to supply data for that decreased polyp recurrence in volunteers also the meta-analysis.
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TON KEYNES Angling Association For 2013 -'14 Society of responsible anglers founded in 1970. Members of the Angling Trust and UOFCA JUST a few of the sort of catches keeping MKAA members happy (left to right) Duncan Menzies 7-6 Stone Park chub Pete Barby sunny afternoon 24lb Furzton mirror Pete Patton 57-6 Lodge bream match catch
Hier finden Sie Fragen und Antworten aus dem Expertenforum "Haarausfall" zum Nachlesen. Ich leide an Alopecia areata und habe meine Kopfhaare und Teile von Augenbrauen und Wimpern verloren. Welche Chancen habe ich, wieder Haare zu bekommen? Gibt es noch andere Heilmethoden außer DCP? Bei einer geringen Ausprägung des kreisrunden Haarausfalls und noch kurzer Erkrankungsdauer kann die Einnahme von Zink hilfreich sein. An die Akutphase kann sich eine Reiztherapie mit Dithranol bzw. Cignolin anschließen, einem äußerlich anzuwendenden Arzneimittel, das sonst in der Behandlung der Schuppenflechte eingesetzt wird. Bei Ihnen handelt es sich jedoch um einen schweren Verlauf mit völligem Haarverlust. Die Wahrscheinlichkeit, ein Nachwachsen der Haare zu erreichen, sinkt mit dem Schweregrad (Ausbreitung und zeitlicher Verlauf) der Alopezie. Auch die Therapie mit der Chemikalie DCP führt nur in weniger als der Hälfte der Fälle zu einem Nachwachsen. Daher ist es bei schweren Formen der Alopecia areata meistens empfehlenswert, sich frühzeitig um eine optimale Zweithaarversorgung zu kümmern.