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* Nutritional Sciences Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Rockville, MD 20892-7328 and A. M. Todd, Inc., Montgomeryville, PA 18936
3 To whom correspondence should be addressed: rosssha{at}mail.nih.gov.
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ABSTRACT |
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 TOP ABSTRACT DISCUSSIONLITERATURE CITED |
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KEY WORDS: • Aberrant crypt foci • colorectal cancer • garlic • allyl sulfur compounds
Colorectal cancer remains an important global health concern, because it has a high mortality rate and its prevalence is increasing. It is the 3rd most prevalent cancer and the 3rd leading cause of cancer deaths in the United States (1). Despite developments in surgical techniques and chemotherapy, there has been only a modest improvement in survival for patients presenting with advanced neoplasms. Effective preventive measures are paramount to minimize morbidity and mortality from this disease; in fact, evidence suggests that diet and bioactive food components are likely to affect the development of colorectal cancer.
Epidemiologic studies found that increased intake of garlic, and/or its active constituents, is associated with reduced colorectal cancer (2–4). For example, results from the Iowa Women's Health Study, a prospective cohort study, found that the strongest association among fruits and vegetables for reduction of colon-cancer risk was for garlic consumption, with an 
50% lower risk of distal colon cancer associated with high consumption (3). Additionally, a meta-analysis of data from 7 epidemiologic studies found an inverse association between raw and cooked garlic consumption and colorectal cancer risk (4). Although the mean intake of garlic per person in the United States is approximately 
0.6 g/wk (3), intakes in areas of China may be as high as 20 g/d (5).
Garlic has long been asserted to possess medicinal properties. Part of its distinction may be associated with sulfur, which can comprise 1% of its dry weight (6). Among the contributors of sulfur in garlic are the allyl sulfur components [e.g., diallyl disulfide (DADS),4 and S-allylcysteine (SAC)], which have been studied extensively for their cancer prevention capacity.
Experimental colon cancer. Colorectal cancer is thought to develop through a series of steps involving genetic and morphological alterations. Numerous studies have focused on the significance of alterations in select crypts as early events in experimental colon carcinogenesis. Aberrant crypt foci (ACF) are early appearing lesions recognized in the colonic surface of rats treated with colon-specific carcinogens such as azoxymethane (AOM) and 1,2-dimethylhydrazine (DMH) (7). The number of ACF increases with time after the carcinogen treatment; they have an increased proliferative activity, and some ACF reveal histological dysplasia (8). ACF similar to those in rodents were also reported in the colonic mucosa in humans (9). Therefore, ACF are regarded as putative preneoplastic lesions for colon cancers and have been used to evaluate potential bioactive food components against colon carcinogenesis (7,10). The potency of an agent (dietary or chemopreventive) to reduce the number of ACF and to reduce the incidence of tumors in the colon of rats is significantly correlated (7). Nevertheless, some inconsistencies occur between tumor development and ACF lesions, suggesting the need for further characterization of the lesion (10). Recent studies have focused on identifying specific histological (i.e., mucin-depleted foci) or molecular (i.e., ß-catenin accumulated crypts) changes to enhance the predictive value of ACF for cancer outcome (11).
Preclinical studies with C57BL/6J mice revealed that the lipid-soluble garlic constituent diallyl sulfide (DAS) given orally before DMH injection significantly reduced the incidence and frequency of colorectal adenocarcinoma (12). In another chemical-carcinogenesis study, the water-soluble garlic constituent SAC inhibited colonic tumors when given 3 h before DMH (13). These findings have encouraged additional research on the mechanism of action of garlic and its constituents in cancer protection. They also have enhanced interest in determining the importance of timing on the anticarcinogenic effect, that is, whether garlic is effective in inhibiting early, preneoplastic lesions.
Protective effect of lipid-soluble allyl compounds in aberrant crypt models. When garlic cloves are disrupted, the enzyme allinase is released; it converts the allin to allicin, a transient compound that quickly rearranges into more stable compounds such as DAS, DADS, and diallyl trisulfide (14). These compounds are primary compounds in preparations containing "garlic oil," although the chemical composition of different preparations varies. Both DAS and DADS were examined for efficacy in inhibiting aberrant crypt formation (15,16). DAS was shown to significantly inhibit ACF in an AOM-induced rat colon model at 1 and 2 g/kg diet (15); DAS was provided 1 wk before injection of the carcinogen and continued throughout the study. These investigators found DAS (79 and 43% of control for DAS when provided at 1 and 2 g/kg diet, respectively) to be less potent than nonsteroidal anti-inflammatory agents (64 and 49% of control for ibuprofen at 0.2 and 0.4 g/kg diet) in inhibiting ACF. The effect of DADS on AOM-induced ACF in rat colon during the postinitiation phase (that is provided in the diet during the last 4 wk of an 8-wk assay) was mixed. In this experiment, DADS at 0.1 g/kg diet, but not at 0.2 g/kg diet, significantly inhibiting ACF (77% of control) (16). Unfortunately, DADS was not examined for activity during the initiation phase by these investigators.
As described above, many studies testing the effect of garlic constituents on aberrant crypt formation have generally shown beneficial effects. However, one study observed an increase in the number of ACF in Fischer 344 rats when DAS (150 or 50 mg/kg) was given by gavage before carcinogen treatment (AOM provided at 20 mg/kg) (17). In that study, rats were killed 10 wk after the last injection of AOM. Rats pretreated with the high-dose gavage administration of DAS exhibited a significant increase in the number of ACF in the distal colon compared with rats administered AOM alone. These investigators also hypothesized that DAS may alter the disposition of AOM or its metabolites in vivo because the compound was shown to modulate phase I and II enzyme activities. An earlier study found that rats administered 1 g/kg DAS in the diet 1 wk before AOM exposure (2 s.c. injections, 15 mg/kg each, 1 wk apart) developed 10% more ACF than colons from the AOM-treated rats fed control diets; the results, however, were not significant (18). The results of these negative findings compared with the other studies might be explained by the large doses of DAS administered, as well as the route and timing of administration of the organosulfur compound.
Protective effect of water-soluble allyl compounds on aberrant crypt foci. SAC is a naturally occurring, water-soluble organosulfur compound derived from garlic, which has been examined for its ability to inhibit aberrant crypt formation in the rat colon. Interestingly, SAC incorporated into the experimental diet (at either 0.125 or 0.25 g/kg diet) of rats significantly decreased the number of ACF by 33 and 54%, respectively, when given during the initiation period (DMH administered i.p. 1 time/wk for 2 wk at 25 mg/kg), but had no effect when given during tumor promotion (19). The anti-initiation property of SAC was suggested to relate to its ability to increase glutathione-S-transferase (GST) and therefore enhance carcinogen detoxification.
SAC was also reported to block AOM-induced tumorigenesis. Adding SAC to the diet at concentrations of 0.125 and 0.25 g/kg reduced aberrant crypt formation by 68 and 46% of control, respectively, when provided during the initiation phase of carcinogenesis (16).
Similar to DMH, the response to SAC did not differ from control when tested in the AOM postinitiation phase. It was previously suggested by these investigators that the effect of SAC during the initiation phase might be due to stimulation of detoxifying enzymes (e.g., GST) and/or inhibition of metabolic activating enzymes (e.g., cytochrome P450), thereby modulating the fate of the carcinogen metabolite that damages DNA (13).
Another laboratory investigated the ability of aqueous solutions of crushed garlic to inhibit ACF (20–22). In studies by Sengupta et al. (20), Sprague-Dawley rats (4–5 wk old) were injected with AOM (3 weekly s.c. injections of 15 mg/kg birth weight) and orally administered a 2% aqueous suspension (wt:v) of garlic starting on d 1 of AOM injection. The garlic suspension was prepared by grinding dehusked cloves of garlic using a mortar and pestle and diluting the resulting paste with water to make a 2% aqueous suspension (wt:v); it was estimated that the rats received 20 mg garlic/d; 12 wk after the first AOM injection, colons were assessed for ACF and compared with the carcinogen control group. The aqueous garlic solution reduced ACF by 32% compared with control fed rats. The investigators replicated these findings and reported that the same dose of garlic inhibited ACF by 45% (21), and in a third study, a 2.5% aqueous suspension (wt:v) of garlic inhibited ACF by 42% (22). Additional findings from this laboratory suggested that the anticarcinogenic potential of the aqueous garlic suspension may be due to modulation of phase II enzymes (e.g., GST) as well as interference with apoptotic and/or proliferative pathways in the colon.
Evaluation of the speciation of allyl compounds on aberrant crypt foci. We recently compared the effect of allyl sulfur compound speciation on ACF (23). Rats were fed a semipurified, casein-based diet with or without 57 or 570 µmol/kg SAC, DADS, or S-allylmercaptocysteine (SAMC), another water-soluble organosulfur constituent found in garlic. Rats were fed their diets for 3 wk before treatment with DMH (25 mg/kg i.p. each week for 2 wk). All rats consumed their assigned diets for 13 wk before determination of ACF and aberrant crypt number (AC). All treatments, except 57 µmol/kg SAC, significantly lowered ACF compared with controls. The AC were significantly reduced by DADS and SAMC at both concentrations tested. Although a diminished body weight may be associated with decreased ACF in rats fed 570 µmol/kg DADS or SAMC, it was not changed by lower exposures and therefore did not account for the reduced aberrations. This study reveals that all allyl sulfur compounds are not equivalent in retarding early preneoplastic markers for colon cancer and also suggests that disulfides are more effective in suppressing ACF and AC. Moreover, this study demonstrates that increasing the exposure 10-fold did not lead to further massive suppression in ACF, suggesting a saturation point for their target. In this study, the allyl sulfurs examined did not greatly influence liver GST activity, suggesting that a shift in the activity of this liver enzyme did not relate to reduced ACF or AC.
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DISCUSSION |
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TOPABSTRACTDISCUSSIONLITERATURE CITED |
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Thus, it is intriguing to speculate that some of the properties of allyl sulfur compounds from garlic may be mediated by Nrf2-ARE promoter interaction with consequent regulation of key phase II enzymes. The recent finding that disulfide garlic constituents (DADS, SAMC) were more potent in the ACF model than the single sulfide compounds (SAC) implicates additional pathways, such as modulation of thiol group biology, in the response to garlic constituents.
Although a systematic analysis has not been performed, many of the garlic compounds tested in the aberrant crypt model (i.e., DAS, SAC, and DADS) were also shown to inhibit chemical carcinogenesis of the colon in rodent models.
In summary, it is clear from several lines of evidence that allyl sulfur compounds from garlic likely influence colorectal cancer at various points in the carcinogenesis pathway (Fig. 1). The ACF assay is not only less expensive and time-consuming than tumor-producing studies, but it also should allow the elucidation of the colon carcinogenic process by exploring the molecular and morphological changes that occur at a precancerous stage.
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FOOTNOTES |
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2 Author disclosure: No relationships to disclose.
4 Abbreviations used: AC, aberrant crypt number; ACF, aberrant crypt foci; AOM, azoxymethane; ARE, antioxidant response element; DADS, diallyl disulfide; DAS, diallyl sulfide; DMH, 1,2-dimethylhydrazine; GST, glutathione-S-transferase; SAC, S-allylcysteine; SAMC, S-allylmercaptocysteine.
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LITERATURE CITED |
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TOPABSTRACTDISCUSSIONLITERATURE CITED |
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