Prevention of colorectal cancer: systematic review of clinical studies in human volunteers; comparison with rats & mice.
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Colon Cancer Prevention, Clinical Trials in Human Volunteers
Comparison of Human Data with Animal Models Data.

- [Man] table is a summary of dietary prevention of colorectal tumors in humans, first published in CEBP. It shows the efficacy of agents or diets to reduce Adenomatous polyp recurrence (Adeno. rec.) or ColoRectal Cancer incidence in humans (CRC incid.).
- [MenRatsMice], another table, compares human data with tumor incidence in azoxymethane initiated rats and polyp number in Min mice. It was published the [Eur.J.Cancer]

See below explanations down on both tables, and comments on the discrepancies down between human's and rodent's studies.

--- How well do the animal models predict what happens in the clinical trials?
To answer this question we built a [MenRatsMice] table showing the effect of dietary interventions on the recurrence of colonic polyps in humans (1), compared with effects on tumors in rats (2) and in mice (3).
(1)- Human data were gathered from randomized, placebo-controlled trials directed at preventing the recurrence of colonic adenomatous polyps in human volunteers: [Man]. Data from each individual study were then summarized as "weighted mean RR/agent", by a simple-minded meta-analysis.
(2)- The mean effect in rats was extracted from the [Tumors] data base of positive studies, to which were added null and negative studies.
(3)- The mean effect in Min mice was calculated from the [Min] data base.
This [MenRatsMice] table is obviously a first approach to such a comparison, since no account was taken of the dose used, and the data presented are not homogeneous across different models. The table, none-the-less, shows that the effect of most of the diets or agents is consistent across the various models though discrepancies are seen between the effect of agents in humans and in animals as explained below.

Comments on Discrepancies

up - NSAIDs strongly decrease the tumor yield in the colon of AOM-injected rats, and in the small intestine of mutant mice. This is consistent with epidemiological studies suggesting that, taken collectively, NSAIDs might decrease the colorectal cancer incidence by 45% in humans. It is also consistent with the effect of celecoxib and sulindac which decrease the polyp number in familial adenomatous polyposis patients trials. However, as detailed in Corpet and Pierre (CEBP, 2003), several independent studies (but not all) show that some NSAIDs can increase the tumor yield in the colon of mutant mice.
- Wheat bran consistently reduces carcinogenesis in animals, but has apparently no significant effect in humans, a discrepancy for insoluble fibers, already pointed out by Giovannucci.
Psyllium, a soluble fiber also called MetaMucil, decreased carcinogenesis in rats (Wilpart 1987), but increased the tumor recurrence in human volunteers (Bonithon 2000). However, both results are only supported by a single study each. An early study showed a strong promotion by psyllium of DMH-induced cancers: most psyllium-treated mice died before control mice (Toth 1984), but mortality data cannot be included in the Chemoprevention Database. In addition, most soluble fibers similar to psyllium show promoting properties in AOM-induced rats: these and Toth's data fit the human trial result.
- Fat: Rats and mice fed a high fat diet have usually more tumors than controls fed a low fat diet. In rodents, the relationship between the colon cancer incidence and the intake of fat remains true when controlled for calorie consumption. Fatty diets with high linoleic acid content, and n-6-polyunsaturated fatty acids, seem particularly consistent promoters in rodents (Zhao 1991). In contrast, neither human trials nor observation studies support fat, or linoleic acid, as tumor promoters in humans (Willet 1995 ), a discrepancy already pointed out by Giovannucci.
- Caloric reduction is a strategy that seems very efficient in animals. Overnutrition could be seen as the most potent "carcinogen" in rodents (Lutz 1992 ). According to Willett (2001), a positive energy balance (caloric intake versus physical activity) is the most powerful and consistent dietary influence on human carcinogenesis. No published human trial specifically tested the effect of caloric reduction. However, a side effect of interventions with low-fat diet, and with fruits and vegetables, was a modest reduction in caloric intake (Schatzkin 2000, McKeown 1994, MacLennan 1995, Beresford 2006). The lack of reduction in polyp recurrence seen in the trials summarized in the [Man] table suggests the caloric reduction was too small to reduce insulin resistance, a link between overnutrition and carcinogenesis that was speculated by Mckeown-Eyssen, 1994, and by Giovannucci, 1995.
- Veg. & Fruits: That fruits and vegetables consumption protects against colorectal cancer is a dogma supported by many epidemiological studies (Gerber 2002 ; WCRF 1997), an association that may have been overstated (Michels 2000). This dogma is challenged by all the experimen­tal studies in rats, mice and humans (see the [Man] table). Indeed, a mixture of fruits and vegetables, reproducing what people typical consume, marginally increased the tumor yield in most animal studies (VanKranen 1998 , Alink 1993, Rijnkels 1997, Rijnkels 1998), although large amounts of black raspberries or of orange juice can inhibit carcinogenesis in rats (Harris 2001, Miyagi 2000).
Conclusion: in spite of the discrepancies, the [MenRatsMice] table, and summary figures, shows that the effect of most of the diets or agents is consistent across the various models.

Explanations and NOTES to the [Man] and [MenRatsMice] tables

NOTES for specific agents (same order as Table's lines: small RRs on top)

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Corpet DE & Taché S, 2002, Nutrition & Cancer - DE Corpet & F Pierre, 2003, Cancer Epidemiol. Biomarkers Prevention - DE Corpet & F Pierre, 2005, Eur.J.Cancer
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