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

Corpet, Denis E.; Pierre, Fabrice H.F.

doi:10.1016/j.ejca.2005.06.006

Cited by 201 publications

(136 citation statements)

References 92 publications

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“…After ACF determination with MB, the samples were stained with HID-AB to highlight mucin production and identify any MDF. As reported in rodents (16)(17)(18)(19), we found that the HID-AB staining allowed a good visualization of the ACF (in Fig. 1, the first and second columns show the same ACF observed in MB-stained and HID-AB-stained colon, respectively).…”

Section: Resultssupporting

confidence: 59%

“…Recently, mucin depleted foci (MDF), formed by dysplastic crypts with scant or absent mucin production, were identified by our group in the colon of rodents treated with azoxymethane or 1,2-dimethylhydrazine (16), which induces CRC through histologic and molecular alterations similar to human carcinogenesis (17). Like ACFs, MDFs are easily identified in unsectioned colon.…”

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confidence: 98%

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Identification of Mucin Depleted Foci in the Human Colon

Femia

Giannini²,

Fazi³

et al. 2008

Cancer Prevention Research

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Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the β-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm 2 ) and at a much lower density in CRC patients (average of 0.0006 lesions/cm 2 ). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.Foci of aberrant crypts (ACF), microscopically visible in the unsectioned colon of carcinogen-treated mice, were originally described by Ranjana Bird in 1987 as being related to the early steps of colon carcinogenesis (1). The results of many studies characterizing ACF (2-4) and the demonstration that ACF-like lesions are also present in humans (5, 6) have reinforced the hypothesis that ACFs are precursors of colon cancer (CRC) and have led to their widespread use as biomarkers of colon carcinogenesis (7, 8). However, reports documenting the heterogeneity of ACF and their relationship with cancer not always straightforward (9-12) opened a debate on the validity of ACF as surrogate end points, stressing the need for additional biomarkers more robustly correlated with cancer (12-15).Recently, mucin depleted foci (MDF), formed by dysplastic crypts with scant or absent mucin production, were identified by our group in the colon of rodents treated with azoxymethane or 1,2-dimethylhydrazine (16), which induces CRC through histologic and molecular alterations similar to human carcinogenesis (17). Like ACFs, MDFs are easily identified in unsectioned colon. Moreover, studies carried out by us and others indicate that MDFs are correlated with carcinogenesis and can thus serve as cancer biomarkers in chemoprevention studies (18-21). We documented that MDFs share pathologic and molecular alterations with more advanced lesions, such as Wnt pathway activation, caused in part by mutations in the β-catenin gene (19). Moreover, the fact that MDFs carry mutations in...

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Section: Resultssupporting

confidence: 59%

mentioning

confidence: 98%

Identification of Mucin Depleted Foci in the Human Colon

Femia

Giannini²,

Fazi³

et al. 2008

Cancer Prevention Research

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“…This promotion by calcium phosphate in a high-fat context was not seen in a low-fat context, in our previous haemin study (6) . It is generally agreed that Ca reduces the risk of colorectal cancer (27) , and a meta-analysis study shows that Ca modestly decreases tumour incidence in rats (28) . However, in fourteen studies out of thirty-two, a non-significant tumour incidence increase was seen in Ca-fed rats.…”

Section: Discussionmentioning

confidence: 99%

Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium

et al. 2008

Self Cite

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Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in rats. We have also shown that dietary Ca, antioxidant mix and olive oil inhibit haemin-induced ACF promotion, and normalize faecal lipoperoxides and cytotoxicity. Here we tested if these strategies are effective also against red meat promotion in dimethylhydrazine-induced rats. Three diets with 60 % beef meat were supplemented with calcium phosphate (31 g/kg), antioxidant agents (rutin and butylated hydroxyanisole, 0·05 % each) and olive oil (5 %). ACF, MDF, faecal water cytotoxicity, thiobarbituric acid reactive substances (TBARS) and urinary 1,4-dihydroxynonane mercapturic acid (DHN-MA) were measured. Beef meat diet increased the number of ACF (þ 30 %) and MDF (þ 100 %) (P,0·001), which confirms our previous findings. Promotion was associated with increased faecal water TBARs ( £ 4) and cytotoxicity ( £ 2), and urinary DHN-MA excretion ( £ 15). Ca fully inhibited beef meat-induced ACF and MDF promotion, and normalized faecal TBARS and cytotoxicity, but did not reduce urinary DHN-MA. Unexpectedly, high-calcium control diet-fed rats had more MDF and ACF in the colon than low-Ca control diet-fed rats. Antioxidant mix and olive oil did not normalize beef meat promotion nor biochemical factors. The results confirm that haem causes promotion of colon carcinogenesis by red meat. They suggest that Ca can reduce colorectal cancer risk in meat-eaters. The results support the concept that toxicity associated with the excess of a useful nutrient may be prevented by another nutrient.

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“…In animal models, dry beans commonly consumed in the United States, such as pinto, black, and navy beans, reduced azoxymethane(AOM)-induced colon adenocarcinomas in F344 rats (20,21); however, the cancer-preventive effect of dry bean fractions are not known. AOM is a carcinogen that is commonly used for animal models of human colon cancer and induces DNA mutations by alkylating DNA primarily at the O 6 -guanidine residues (22,23).…”

Section: Introductionmentioning

confidence: 99%

Dietary Cooked Navy Beans and Their Fractions Attenuate Colon Carcinogenesis in Azoxymethane-InducedOb/ObMice

Bobe

Barrett

Mentor-Marcel

et al. 2008

Nutrition and Cancer

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Based on the protective effects of cooked dry bean consumption in a human intervention study, we evaluated which fraction of cooked dry beans is responsible for its cancer-preventive effects. Cooked navy beans (whole beans), the insoluble fraction (bean residue) or soluble fraction of the 60% (vol:vol) ethanol extract of cooked navy beans (bean extract), or a modified AIN-93G diet (16.6% fat including 12.9% lard) as control diet were fed to 160 male obese ob/ob mice after 2 azoxymethane injections. In comparison to control-fed mice, dysplasia, adenomas, or adenocarcinomas were detected in fewer mice on either bean fraction diet (percent reduction from control: whole beans 54%, P = 0.10; bean residue 81%, P = 0.003 ; bean extract 91%, P = 0.007) , and any type of colon lesions, including focal hyperplasia, were found in fewer mice on each of the 3 bean diets percent reduction from control: whole bean 56%, P = 0.04; bean residue 67%, P = 0.01; bean extract 87%, P = 0.0003. These results suggest that both the soluble and the insoluble fraction of the extract contribute to the cancer-protective effect of cooked navy beans.

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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

Cited by 201 publications

References 92 publications

Identification of Mucin Depleted Foci in the Human Colon

Identification of Mucin Depleted Foci in the Human Colon

Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium

Dietary Cooked Navy Beans and Their Fractions Attenuate Colon Carcinogenesis in Azoxymethane-InducedOb/ObMice

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