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4 Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5000 Australia; 5 Department of Nutrition and Dietetics, Flinders University, Adelaide, 5001 Australia; 6 Preventative Health National Research Flagship CSIRO, Adelaide, 5000 Australia; and 7 School of Science and Primary Industries, Charles Darwin University, Casuarina Campus, Darwin, 0909 Australia
* To whom correspondence should be addressed. E-mail: suong.ngo{at}cdu.edu.au.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMethodsResults and DiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMethodsResults and DiscussionLITERATURE CITED |
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12,600 new cases and 4700 deaths each year (4). Approximately 1 in 21 Australians is likely to develop CRC during his/her lifetime and the risk is higher after the age of 40 and increases progressively from 50 y of age. The latest available national figure showed that CRC was responsible for 13% of cancer deaths in 2001, with an estimated 29,058 life-years lost from premature death before the age of 75 y (4). Most CRC are thought to develop from slowly growing benign polyps (4,5). Environmental factors have a great influence on the multiple-stage process that leads from the precursor lesion to cancer (6) and nutritional intervention has been identified as playing a major role in its prevention (7). Vegetables and certain bioactive plant components possess protective effects on the development of CRC, with research interest focusing on garlic in recent years.
Garlic (Allium sativum) belongs to the vegetables of the Allium genus that is characterized by a high content in organosulfur compounds and flavonoids. Depending on the conditions of its cultivation, garlic may contain at least 33 different organosulfur compounds in addition to amino acids, vitamins, and micronutrients. The allyl sulfur constituents in garlic, which comprise 1% of its dry weight, are responsible for its health benefits (8–17). The major allyl sulfur content in freshly crushed/chopped/cut garlic is allicin, which is unstable and breaks down rapidly to produce odorous oil-soluble diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), and ajoene. The major allyl sulfur constituents in processed garlic, such as aged garlic extract (AGE), include S-allylcysteine (SAC) and S-allylmercaptocysteine, which are water soluble and formed by the process of natural aging bioconversion (14).
Garlic has been widely cultivated and used worldwide for its apparent health benefits for thousands of years. Garlic has been considered to increase longevity and physical strength and found to possess numerous medicinal properties, including antimicrobial, antithrombotic, hypolipidemic, antiarthritic, hypoglycemic, and antitumor effects (13,14,18–35). Recently, much research interest has focused on the pharmacological properties of garlic and its active constituents, particularly with regard to their effects on the prevention of cancer. In addition to the major allyl sulfur contents, other constituents with antioxidant properties and/or anticarcinogenic activity, including flavonoids (particularly kaempferol), selenium, vitamins A and C, arginine, and fructooligosaccharides are also found in garlic. It is likely that these constituents also contribute to the overall health benefits attributed to garlic (1,8–17,35). In general, fresh garlic contains water, carbohydrates, proteins and fiber, fats, and several essential amino acids, minerals, vitamins and micronutrients. The intake of garlic in humans worldwide varied greatly between countries. Overall, the intake ranged from no consumption to intake of >5 cloves/wk (15 g or 5 servings/wk). One serving was considered equal to 1 clove of garlic, which is 3 g. Published human studies demonstrating this wide range of garlic intake is summarized and analyzed in the "Results and Discussion." No symptoms of garlic toxicity were reported in the literature.
Garlic and its allyl sulfur constituents have been reported to exert their protective effects on colonic carcinogenesis in animal and in vitro studies by several mechanisms, including inhibition of carcinogen-induced DNA adduct formation (36), blockage of cell growth, blockage of cell proliferation, and blockage of angiogenesis (18–20,22–30,32,33,37–42), induction of differentiation and/or apoptosis (8,19,22,23,25,27,34,40,41,43–45), enhancement of carcinogen-detoxifying enzymes (27,29,41) and/or suppression of carcinogen-activating enzymes (21,31), inhibition of cyclooxygenase-2 expression (40), scavenging carcinogen-induced free radicals (14), and inhibition of lipid peroxidation (41). Not only are the major sulfur compounds important in the overall protective effects of garlic against cancers but so too are other constituents described previously, including kaempferol, selenium, vitamins A and C, arginine, and fructooligosaccharides (1,9,12–17,35). The aim of this study was to evaluate and review systematically the scientific evidence derived from all types of studies published over the last decade that examined the effects of garlic and/or garlic active constituents on CRC. This article identifies if there are gaps in existing information and provides future directions for research.
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Methods |
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TOPABSTRACTIntroductionMethodsResults and DiscussionLITERATURE CITED |
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Human trials. For a human trial to be included in this review, study subjects must have had at least 1 baseline endoscopic procedure for the outcome of adenomatous polyps and the final outcomes needed to have been identified by direct visualization by colonoscopy and confirmed pathologically. In all cases, at least 1 of the primary outcomes must have been reported.
Ranking of outcome measures. Outcomes were rated according to a hierarchy of outcome measures, adapted and modified from those used by the National Health and Medical Research Council (NHMRC) Australia (46–48). Subject relevant clinical outcomes (primary outcomes) were rated level 1; surrogate outcomes (secondary outcomes; intermediate outcomes being predictive of clinical outcomes) were rated level 2; and measurable variables with an indirect connection to the target outcomes were rated level 3 (details of the ranking of outcome measures are summarized in Table 1).
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Quality assessment. The quality of studies was assessed against a set of quality criteria, adapted and modified from those used by the NHMRC (47,48) and the Cochrane Collaboration (49) (details of the quality criteria are summarized in Table 2). Based on the methodology and results as they appeared in the publications, each criterion received a grade A if the assessed criterion was adequately conducted. Grades B, C, or D corresponded to whether the assessed criterion was unclear, inadequate, or not conducted, respectively.
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Due to great differences in study designs of human dietary intervention trials as well as the diversity of the types of studies collected, no formal statistical analysis was performed.
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Results and Discussion |
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TOPABSTRACTIntroductionMethodsResults and DiscussionLITERATURE CITED |
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Only 1 RCT of CRC incidence (level II evidence) in English was identified from the last 10 y. There were 2 publications on this RCT that examined different types of outcomes (detailed in Table 1); the study published in 2006 reported a significant suppression in both the total size and number of adenomas in CRC patients taking AGE (50) and the study published in 2004 reported a 29% reduction in developing at least 1 new adenoma in these patients, with a reported relative risk of 0.71 (51). These results were based on a relatively small sample of 37 patients with CRC. In the 2004 and 2006 studies, 51 patients were randomized to high or low AGE and given 3 capsules twice per day (2.4 mL or 0.16 mL USP) garlic fluid extract (52); 76% of the treated and 69% of the control group completed the 12-mo trial, with 12 patients withdrawn within 6 mo due to poor follow-up colonoscopies, not following test protocol, or having personal or family issues (50,51).
Five case control (53–57) and 3 cohort studies (58–60) of CRC (level III evidence) were identified. All of the studies were rated as high quality. Overall, 5 of the 8 high quality human studies suggested a protective effect of a high intake of garlic. One published meta-analysis (level III evidence) of 7 of these case control/cohort studies was indentified that confirmed this inverse association, with a reported 30% reduction in CRC relative risk (61). The meta-analysis excluded the largest study that showed no association. One case control study focused on colorectal polyps as opposed to CRC (55). These studies were conducted in Switzerland (53), the United States (54,55,58,59), Argentina (56), China (57), and the Netherlands (60) and measured raw and cooked garlic intake. One cohort study examined garlic supplement (60) and 1 case control study combined raw cooked garlic with onions and peppers into a single exposure category (56). The relative risk estimate, 95% CI, P-value, year of publication, country and number of subjects, garlic categorization, and adjustment for covariates were abstracted from these studies (Supplemental Tables 1 and 2).
The size of the 3 cohort studies ranged from over 3100 participants to 48,000 participants; 1 cohort study included both male and female populations (60), whereas the other 2 examined either male (59) or female populations (58). Participants for 3 of the 5 case control studies were recruited from hospitals (53,55,57) and the other 2 case control studies included population controls (54,56). Sample sizes of the case control studies ranged from 109 to 698 cases, with a participation rate of 66–92% for cases and 71–86% for controls. In 1 case control study, the participation rate appeared to be 100% (57). The main reasons for nonparticipation included death before contact (54,56), severe illness (54,56), refusal (53–56), or inability to locate the subject (54,55). With regard to control selection bias, cases were pathologically confirmed by colonoscopy in all case control and cohort studies and were linked with a cancer registration system in 4 of the case control and cohort studies (53,54,58,60). The main inclusion criteria for the comparison (or control) group or cohort included no history of CRC or polyps, no cancer (other than skin cancer), no severe gastrointestinal conditions, or no conditions related long-term modification of diet at baseline (53–56,31–33). In addition, 4 of the case control studies demonstrated a satisfactory participation for cases and controls of >80% and the follow-up rate of the cohort studies was 80 (59) to 95% (59,60).
With respect to control information bias and confounding, all case control and cohort studies utilized some form of FFQ that was previously validated and/or used. The questionnaire collected information on the frequency of usual intake of foods during 1- (55,58–60) 2- (53), 3- (54), or 5-y periods (56) prior to interview. In 6 of the 8 studies, the number of food items ranged from over 125 items to over 280 items and 2 case control studies utilized a FFQ comprising 25 (57) or 79 items (53). In all studies, the type of food items, food categorization, and how food intake was standardized and measured were described adequately. For example, most studies reported the names of food items, the types of measures (such as portion sizes, measuring spoons, and cups being used in the FFQ), and how they were used to facilitate quantification of intake as well as method for calculation of intake, etc. There was considerable variability in the measure of food intake between studies. For example, the highest intake category reported in 1 study was >14.27 g/wk (56), whereas in another study it was >3 g/wk (58); some did not provide specific quantitative cutoffs (53,57).
The majority of the studies adjusted for several covariates, including age (53,54,56,58–60), sex (53,56,60), history of CRC (54,59,60), total energy intake (53–55,58,59), tobacco (53–55,58–60), alcohol (53,54,58), BMI (53,55,58), physical activity (53–55,58), education (53,58,60), and race (55). One case control study did not adjust for other factors (57).
Five of 8 of the case control and cohort studies showed an inverse association for the highest intake of raw/cooked garlic and colon and/or rectal cancers compared with no intake. Two case control studies demonstrated a strong protective effect for both the highest and medium intake compared with no intake [OR, 95% CI: 0.32, 0.18–0.57 and 0.51, 0.35–0.74, respectively (53)] or OR, 95% CI: 0.22, 0.10–0.51 and 0.44, 0.19–0.91, respectively, in which garlic, onion, and peppers were incorporated into 1 category (56). One case control study showed a strong inverse association for the highest intake compared with no intake (OR, 95% CI: 0.21, 0.05–0.84) that was based on only 109 cases and 109 controls (57). In addition, 1 case control study reported a significant protective effect for the highest intake on incidence of colorectal polyps (OR, 95% CI: 0.63, 0.42–0.95) (55). Only 1 case control study found weak evidence of an inverse association for men (OR, 95% CI: 0.7, 0.5–1.1) and no association for women; these results were unchanged after adjustments for several covariates (54).
Two of the 3 cohort studies included in this review were large U.S. studies that indicated a strong inverse relationship for the highest intake of garlic compared with no intake and colon cancer [relative risk (RR), 95% CI: 0.65, 0.44–0.97] in which a stratified analysis of the distal colon showed an approximate 48% lower risk of colon cancer observed for the highest intake in comparison with no intake of garlic (58) or RR, 95% CI: 0.63, 0.38–1.65, but this finding is not significant and was limited to the distal colon only (59). Only 1 cohort study, examining garlic supplement, did not find an inverse association; it did, however, detect a nonsignificant slightly lower risk for colon and rectal cancer (RR, 95% CI: 0.93, 0.51–1.71 and 0.77, 0.41–1.46, respectively), which was based on only 443 colon and rectal cases, respectively (60).
Due to great heterogeneity of measures of intake among case control and cohort studies, it is not possible to determine the minimum intake of garlic necessary to exhibit a protective effect. Overall, the case control and cohort studies demonstrated a consistent inverse association between a high garlic intake and CRC.
Animal studies.
Eleven animal studies of carcinogen-induced colonic tumorigenesis (level V evidence) were identified and included in this review (details are summarized in Supplemental Tables 3–5). These studies reported a significant protective effect of garlic and/or its allyl sulfur constituents. Similar to human studies, most animal studies examined level 1 outcomes that were subject-relevant clinical outcomes. Overall, most animal studies demonstrated a significant reduction in the incidence and/or growth and multiplicity of carcinogen-induced tumors or a significant reduction in the number of tumor biomarker aberrant crypt foci (ACF), particularly ACF with 
4 aberrant crypts. One study emphasized effects in the small intestine rather than the colon (39). Although most animal studies mainly utilized ACF as the endpoint, the results obtained in these studies with regard to ACF number/rat were quite contradictory. The findings suggested the potential caveats of emphasis on ACF as the endpoint in animal models of carcinogen-induced colonic carcinogenesis.
Both lipid and water soluble allyl sulfides were effective in suppression of colonic carcinogenesis in a dose- and time-dependent manner. The response to garlic/garlic constituent treatment differed little in animal studies of carcinogen-induced tumorigenesis, whereas the antiproliferative and apoptotic effects appeared to be dependent on the presence of sulfur molecules and whether the agent was lipid or water soluble allyl sulfides. Moreover, colorectal tumors did not respond equally to different garlic allyl sulfur constituents (12). DATS was >10 times more effective than DADS in suppressing colonic tumors (44).
The anticancer properties were detected mainly for AGE (39), garlic suspension (40,41), garlic power (36), and allyl sulfur constituents SAC (62,63), DADS (42,64), DAS (65,66), and DATS (44), with a less significant effect observed for SAMC. Other anticarcinogenic effects reported by animal studies included: induction of apoptosis by garlic extract (40,41), DAS (66) inhibition of CRC cell proliferation by garlic extract (40,41) and AGE (39), inhibition of carcinogen-induced DNA adduct formation by garlic powder (36), enhancement of carcinogen-metabolizing enzymes by garlic extract (41), inhibition of cyclooxygenase-2 expression by garlic extract (40) and DAS (66), and inhibition of lipid peroxidation by garlic extract (41). The reported minimum amounts of DATS, DADS, SAC, and DAS that were required to bring about the response were 6, 100, 125, and 1000 mg/kg body weight daily, respectively (44, 62–65). The identified animal studies have provided important insight into the mechanisms of CRC protection by garlic and its active allyl sulfur constituents. No significant adverse effects have been reported in any of the identified studies.
In summary, there is substantial and consistent scientific evidence derived from RCT (level II) of animal studies (level V) demonstrating protective effects of AGE, fresh garlic extracts, and active garlic organosulfur constituents against CRC despite great heterogeneity of measures of intakes among human epidemiological studies. The findings suggested that garlic must be considered as part of the entire diet. It is likely that dietary patterns have important influences on the response to garlic. The literature has suggested that a diet high in red meat and fat may increase an individual's risk of getting CRC (67), whereas other micronutrients such as folate; methionine; vitamins B-6, B-12, C, and E; selenium; and lycopene have been found to be protective for CRC (68). Given the small sample size examined by the current RCT, future RCT is warranted to better confirm the protective effect of garlic in CRC.
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FOOTNOTES |
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2 Author disclosures: S. N. T. Ngo, D. B. Williams, L. Cobiac, and R. J. Head, no conflicts of interest.
3 Supplemental Tables 1–5 are available with the online posting of this paper at jn.nutrition.org.
8 Abbreviations used: ACF, aberrant crypt foci; AGE, aged garlic extract; CRC, colorectal cancer; DADS, diallyl disulfide; DAS, diallyl sulfide; DATS, diallyl trisulfide; NHMRC, National Health and Medical Research Council; RCT, randomized control trial; RR, relative risk; SAC, S-allylcysteine.
Manuscript received 14 May 2007. Initial review completed 31 May 2007. Revision accepted 13 July 2007.
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