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* Department of Pathology and Microbiology, University of South Carolina School of Medicine and South Carolina Cancer Center, Columbia, SC 29203 and Department of Epidemiology and Biostatistics, Norman J. Arnold School of Public Health, University of South Carolina and South Carolina Cancer Center, Columbia, SC 29208
2 To whom correspondence should be addressed. E-mail: michael.wargovich{at}palmettohealth.org.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • diet • cancer • polymorphisms • thrifty gene • feast and famine
Diet and cancer in the 1980s
About 20 years ago, the first dietary recommendations were made available to the general public, based on a number of epidemiological studies conducted during the 1970s and early 1980s ( 1). These were largely studies comparing measures of intake of food items and nutritional patterns between countries of high incidence and lower incidence for cancer. From these studies, it was generally concluded that diet did in fact play a large role in human cancer. Probably the most consistent finding was that of an inverse relationship between risk for certain common cancers and intake of fruits and vegetables, whole grain cereals, and some types of fat such as those with (n-3) fatty acids ( 2). From these findings, governmental bodies and preventive health organizations counseled the public to reduce fat intake, particularly animal fats, increase fiber intake (whole grains suggested), consume a variety of vegetables and fruits, consume salt and alcohol in moderation and be physically active.
The evidence for the dietary recommendations has been considered strong in the case of vegetable and fruit intake, but more controversial for other foods. For fruits and vegetables, the great majority of cohort studies and case-control studies support reduced risk for cancer when consumption is persistent. Data appear strongest for cancers of the mouth, stomach, colon and lung ( 3).
In the case of dietary fiber, epidemiological studies suggest that colorectal and breast cancer risk may be decreased by increasing the intake of dietary fiber and phytochemical-rich foods, cereals and whole grains but findings are not entirely consistent ( 4). Some studies include observations pertaining to fiber from fruits and vegetables. The data on wheat bran as a possible preventive agent are supported by animal studies, specifically rodent models for colon cancer ( 5, 6). However, two large randomized controlled clinical trials failed to find a strong protective effect for wheat bran in the prevention of recurrent adenomatous polyps in the colon ( 7, 8).
The Polyp Prevention Trial, recently completed by the National Cancer Institute, randomized >2,000 men and women older than age 35, who had undergone polypectomy within 6 mo, into two groups. The first group was assigned to an intensive intervention, counseled to follow a diet low in fat (with a target of 
20% fat) and high in fiber (18 g of fiber for every 1,000 calories consumed). Some of the fiber to be gained came from a minimum of at least three and one-half servings of fruit and vegetables for every 1,000 calories. The other group was given a brochure about dietary recommendations and individuals were asked to follow their usual diet. Colonoscopy was repeated in all of the study subjects 1 and 4 y after the start of the study. At the end of the study, the intervention group had successfully lowered fat intake, increased fiber content of their diet and increased their intake of fruits and vegetables relative to the information-only group. However, the recurrence rates of polyps in both groups were similar, leading to the conclusion that no impact on polyp prevention had been made by dietary changes of even 4-y duration (
9). This has been widely interpreted by the lay public that such dietary changes have no impact on the prevention of cancer.
In another colon polyp prevention study, individuals 40–80 y of age who had recently had a polyp removed were randomized to consume either a supplement of 13.5 g of wheat-bran fiber on a daily basis, or only 2 g of supplementary wheat bran. Again, at the end of the 3-y intervention it was concluded that no reduction in formation of subsequent polyps was afforded by the bran diet ( 7).
During the 1980s, vitamins were suspected to aid in the prevention of cancer, and great weight was placed on the evidence for ß-carotene as a very promising cancer-preventive agent. Epidemiologic studies suggested that eating foods rich in ß-carotene was strongly associated with a reduced risk for certain cancers, especially lung cancer ( 10). Animal studies also implied that ß-carotene, a proxy for green and yellow vegetables, was chemopreventive ( 11). Highly unexpected were the results of two large intervention trials that used ß-carotene as an intervention in populations of smokers and/or asbestos-exposed individuals. Both trials found lung cancer risk to increase upon supplementation with ß-carotene, suggesting that in humans ß-carotene also could have pro-oxidant activity ( 12, 13).
With the failure of these large-scale clinical trials to prevent preneoplasia or cancer, the public has widely interpreted the dietary recommendations for the prevention of cancer as unsupported by the research. Yet, some successes have been evidenced in getting the message across. For instance, the National Institutes of Health 5-A-Day Program has raised awareness of inclusion of fruits and vegetables in the daily diet in low socioeconomic populations and in youths ( 14). However, the lack of a protective effect in recently conducted diet and cancer trials raises the question of whether dietary change is applicable at the level of the individual, and whether purposeful externally driven intellectualized dietary change can have the same effects on disease risk as habitual patterns of consumption driven by the internal factors of physiology and psychology.
Why dietary changes may not imply a health benefit at the level of an individual
Cytochrome P450s are members of a very large gene family encoding enzymes that govern the metabolism (known also as phase-1 reactions) of carcinogens and drugs from inactive to highly reactive ( 15). Various cytochromes are involved in the metabolism of carcinogens and procarcinogens found in human diets ( Table 1). For instance, CYP1A1 plays a central role in the metabolism of polycyclic aromatic hydrocarbons that are found in foods exposed to open flame ( 16). CYP1A2 has affinity for another class of dietary carcinogens, the heterocyclic amines (HCA)3 found in thermally oxidized meat protein ( 17). CYP2E1 influences both the activation of many nitrosamines and metabolism of elements in foods that modify this P450 isoform's activity, such as in allium vegetables ( 18). Polymorphisms in CYP genes in general, and CYP1A1 and CYP1A2 in particular, could account for increased or decreased enzyme activity, and thus modify risk if one is exposed to substrates for these cytochromes. Studies in smokers regarding the CYP1A1 polymorphism Msp1 suggest an increased risk for lung cancer ( 19). On the other hand, certain compounds found in cruciferous vegetables have been found to increase CYP1A1 activity, potentially altering the metabolism of estrogen, and thus modify risk for breast cancer ( 20). Similarly, risk for gastric cancer has been reported to be modulated in both directions when individuals carrying the Rsa 1 polymorphism in CYP2E1 were genotyped relative to individuals without gastric cancer ( 18). Considerable research has been conducted on the role of polymorphisms in the phase 2–detoxification enzymes. Glutathione-S-transferases (GST) are a family of enzymes that detoxify reactive electrophiles ( 21). For example, the GSTM1 isoform may play a role in the elimination of metabolites of benzo[a]pyrene, which is found in tobacco smoke. An increased risk for lung cancer has been found for individuals with polymorphisms in GSTM1 and GSTT1 isoforms but again, these data are not consistent ( 22). Of great interest is the hypothesis that isothiocyanates, cancer chemopreventive compounds found in cruciferous vegetables, also are metabolized by GST. In individuals polymorphic for GSTM1 or GSTT1, isothiocyanates may be eliminated from the body at much slower rates than in individuals with wild-type genes for GST. In a Chinese cohort study, London et al. ( 23) found that in individuals with a homozygous deletion in both GSTM1 and GSTT1 had a reduced risk for lung cancer as compared to those without the deletion, and this correlated with urinary excretion of isothiocyanates.
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The gene encoding methylenetetrahydrofolatereductase (MTHFR) is subject to polymorphisms that affect the metabolites of folate and their distribution in vivo. One well-studied interaction is the C677T MTHFR polymorphism and folate levels. MTHFR catalyzes the irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyl tetrahydrofolate, the major form of circulating folate. Individuals homozygous for the C677T phenotype have an 30% reduction in enzyme activity, and may need increased levels of dietary folate to maintain adequate tissue levels of this vitamin, particularly in the presence of elevated alcohol consumption (
27). On the other hand, reduced activity of the MTHFR enzyme also may increase the likelihood of sufficient methylation of dUMP to dTMP, resulting in less misincorporation of uracil into DNA, fewer DNA strand breaks and a decreased risk for cancer. Additional studies of this observation suggest that the MTHFR mutation as well as the folate status in cells modulate the risk of developing various cancers including colorectal cancer (
27).
Feast or famine: the consequences of chronic "feasting" on risk for cancer
Despite the best of intentions and massive educational programs of national and federal health agencies to counsel Americans to eat a healthy diet, the proportion of overweight and obese Americans is steadily increasing ( 28). Several interesting hypotheses are being pursued in other health fields pertaining to how diet and lifestyle changes have combined in modern cultures to lead to increased risk for cardiovascular disease and diabetes. One hypothesis is that during much of our evolution we experienced periodic, often unpredictable, cycles of feast and famine but now live in a state of constant "feasting." According to this concept, individuals with a "thrifty" genotype are more efficient at metabolic pathways that lead to conversion of calories to fat tissue during times of feasting, and this would have had a survival benefit in long periods or repeated food shortages during development of our species ( 29). Enlarging upon this hypothesis, we see that, until relatively recent times, the human condition was characterized by periodic episodes of feasting and famine, while governed by strong diurnal and annual rhythms, and strongly influenced by moderate to intensive physical activity. Industrialization in the late 19th and 20th centuries has led to a marked reduction in physical activity levels for most people. In most developed countries, physical activity is now generally relegated to a part-time leisure activity rather than a steady daily activity found in the workplace. In the U.S., electrification in the 1940s eliminated the limitation of workplace hours and other indoor activities to the length of the solar day. Since the early 1950s, the fast-food industry has provided easy access to calories, made them very affordable and then "supersized" them. In parallel with this phenomenon, portion sizes have been increasing to the point where one meal is often sufficient for two people. Since the 1980s, the explosion of low-fat foods has led to increased ease of overconsumption of refined carbohydrates. Taken together, (as shown in Table 2) these developments likely contribute to the increasing percentage of Americans (and residents of other Westernized countries) who are either overweight or obese. The continued presence of inherited "thrifty" genes may exacerbate this tendency in present day individuals who carry it.
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The rise in the availability of low-fat foods may have had an unintentional side effect of contributing to the epidemic of obesity in this and in other developed countries where physical activity is in decline. It is hypothesized that dietary patterns that include low-fat foods with a concomitant increase in refined carbohydrates could lead to insulin resistance and may relate to an increased risk for some cancers, notably colon cancer. The mechanism involved appears to involve insulin itself, and insulin-like growth factor (IGF) and its associated binding proteins; higher levels of insulin and IGF-1 have been linked to increased colon cancer risk ( 33).
In women at least, android obesity itself appears to be associated with the elevation of lipid peroxidation and persistent platelet activation, driven by inflammatory triggers, and at least partially reversible upon successful weight loss ( 34). This and observations in animal studies of caloric restriction and availability suggest that profound physiological alterations accompany the disruption of evolutionarily "normal" relationships with unstable or minimal food availability ( 35). In such a context of overabundance, it may therefore be entirely unreasonable to expect that simple dietary changes aimed at increasing consumption of "good" nutrients such as those found in fruits and vegetables, and reducing "bad" nutrients such as fat, can have the desired effect of reducing the risk for diseases, such as cancer, that are typical of the rich industrialized world of overabundance. Accomplishing this goal at the level of the individual may well require profound alteration in the way we think about food, and in the greater nutritional and lifestyle context in which individuals make food choices.
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FOOTNOTES |
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3 Abbreviations used: GST, glutathione-S-transferase; HCA, heterocyclic amine; IGF, insulin-like growth factor; MTHFR, methylenetetrahydrofolatereductase; NAT, N-acetyltransferase.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
|---|
1. National Research Council. (1982) Diet, nutrition, and cancer. pp. 51–202. National Academy Press, Washington, DC.
2. American Institute for Cancer Research and World Cancer Research Fund. (1997) Food, nutrition and the prevention of cancer: a global perspective. pp. 362–421. American Institute for Cancer Research, Washington, DC.
3. Greenwald, P., Clifford, C. K. & Milner, J. A. (2001) Diet and cancer prevention. Eur. J. Cancer 166: 948–965.
4. Potter, J. D. & Steinmetz, K. (1996) Vegetables, fruit and phytoestrogens as preventive agents. IARC Sci. Publ. 139: 61–90.
5. Weisburger, J. H., Reddy, B. S., Rose, D. P., Cohen, L. A., Kendall, M. E. & Wynder, E. L. (1993) Protective mechanisms of dietary fibers in nutritional carcinogenesis. Basic Life Sci. 61: 45–63.[Medline]
6. Lupton, J. R. (2000) Is fiber protective against colon cancer? Where the research is leading us. Nutrition 16: 558–561.[Medline]
7. Alberts, D. S., Martinez, M. E., Roe, D. J., Guillen-Rodriguez, J. M., Marshall, J. R., van Leeuwen, J. B., Reid, M. E., Ritenbaugh, C., Vargas, P. A., Bhattacharyya, A. B., Earnest, D. L. & Sampliner, R. E. (2000) Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N. Engl. J. Med. 342: 1156–1162.
8. MacLennan, R., Macrae, F., Bain, C., Battistutta, D., Chapuis, P., Gratten, H., Lambert, J., Newland, R. C., Ngu, M. & Russell, A. (1995) Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. The Australian Polyp Prevention Project. J. Natl. Cancer Inst. 87: 1760–1766.
9. Schatzkin, A., Lanza, E., Corle, D., Lance, P., Iber, F., Caan, B., Shike, M., Weissfeld, J., Burt, R., Cooper, M. R., Kikendall, J. W. & Cahill, J. (2000) Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N. Engl. J. Med. 342: 1149–1155.
10. van Poppel, G. & Goldbohm, R. A. (1995) Epidemiologic evidence for beta-carotene and cancer prevention. Am. J. Clin. Nutr. 62: 1393S–1402S.
11. Kelloff, G. J., Boone, C. W., Crowell, J. A., Steele, V. E., Lubet, R. & Sigman, C. C. (1994) Chemopreventive drug development: perspectives and progress. Cancer Epidemiol. Biomarkers Prev. 54: 85–98.
12. Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Jr., Valanis, B., Williams, J. H., Jr., Barnhart, S., Cherniack, M. G., Brodkin, C. A. & Hammar, S. (1996) Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl. Cancer Inst. 88: 1550–1559.
13. Albanes, D., Heinonen, O. P., Huttunen, J. K., Taylor, P. R., Virtamo, J., Edwards, B. K., Haapakoski, J., Rautalahti, M., Hartman, A. M., Palmgren, J. & Greenwald, P. (1995) Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am. J. Clin. Nutr. 61: 1427S–1430S.
14. Stables, G. J., Subar, A. F., Patterson, B. H., Dodd, K., Heimendinger, J., Van Duyn, M. A. & Nebeling, L. (2002) Changes in vegetable and fruit consumption and awareness among US adults: results of the 1991 and 1997 5 A Day for Better Health Program surveys. J. Am. Diet. Assoc. 102: 809–817.[Medline]
15. Kaminsky, L. S. & Spivack, S. D. (1999) Cytochromes P450 and cancer. Mol. Aspects Med. 137: 70–84.
16. Autrup, H. (2000) Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response. Mutat. Res. 464: 65–76.[Medline]
17. Landi, M. T., Sinha, R., Lang, N. P. & Kadlubar, F. F. (1999) Human cytochrome P4501A2. IARC Sci. Publ. 148: 173–195.
18. Novak, R. F. & Woodcroft, K. J. (2000) The alcohol-inducible form of cytochrome P450 (CYP 2E1): role in toxicology and regulation of expression. Arch. Pharm. Res. 23: 267–282.[Medline]
19. Crofts, F., Taioli, E., Trachman, J., Cosma, G. N., Currie, D., Toniolo, P. & Garte, S. J. (1994) Functional significance of different human CYP1A1 genotypes. Carcinogenesis 12: 2961–2963.
20. Kristensen, V. N., Kure, E. H., Erikstein, B., Harada, N. & Borresen-Dale, A. (2001) Genetic susceptibility and environmental estrogen-like compounds. Mutat. Res. 482: 77–82.[Medline]
21. Nair, U. & Bartsch, H. (2001) Metabolic polymorphisms as susceptibility markers for lung and oral cavity cancer. IARC Sci. Publ. 154: 271–290.[Medline]
22. Risch, A., Wikman, H., Thiel, S., Schmezer, P., Edler, L., Drings, P., Dienemann, H., Kayser, K., Schulz, V., Spiegelhalder, B. & Bartsch, H. (2001) Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas. Pharmacogenetics 11: 757–764.[Medline]
23. London, S. J., Yuan, J. M., Chung, F. L., Gao, Y. T., Coetzee, G. A., Ross, R. K. & Yu, M. C. (2000) Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet 356: 724–729.[Medline]
24. Hein, D. W. (2000) N-Acetyltransferase genetics and their role in predisposition to aromatic and heterocyclic amine-induced carcinogenesis. Toxicol. Lett. 112: 349–356.
25. Hein, D. W. (2002) Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis. Mutat. Res. 506: 65–77.
26. Probst-Hensch, N. M., Haile, R. W., Ingles, S. A., Longnecker, M. P., Han, C. Y., Lin, B. K., Lee, D. B., Sakamoto, G. T., Frankl, H. D., Lee, E. R. & Lin, H. J. (1995) Acetylation polymorphism and prevalence of colorectal adenomas. Cancer Res. 55: 2017–2020.
27. Choi, S. W. & Mason, J. B. (2002) Folate status: effects on pathways of colorectal carcinogenesis. J. Nutr. 132: 2413S–2418S.
28. Public Health Service. (2001) The surgeon general's call to action to prevent and decrease overweight and obesity. Pub. No. 017–001–0051–7, U.S. Department of Health and Human Services, Washington, DC.
29. Booth, F. W., Chakravarthy, M. V., Gordon, S. E. & Spangenburg, E. E. (2002) Waging war on physical inactivity: using modern molecular ammunition against an ancient enemy. J. Appl. Physiol. 93: 3–30.
30. Schernhammer, E. S., Laden, F., Speizer, F. E., Willett, W. C., Hunter, D. J., Kawachi, I. & Colditz, G. A. (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. J. Natl. Cancer Inst. 93: 1563–1568.
31. Nie, D. & Honn, K. V. (2002) Cyclooxygenase, lipoxygenase and tumor angiogenesis. Cell. Mol. Life Sci. 59: 799–807.[Medline]
32. Fitzpatrick, F. A. (2001) Inflammation, carcinogenesis and cancer. Int. Immunopharmacol. 1: 1651–1667.[Medline]
33. Giovannucci, E. (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J. Nutr. 131: 3109S–3120S.
34. Davi, G., Guagnano, M. T., Ciabattoni, G., Basili, S., Falco, A., Marinopiccoli, M., Nutini, M., Sensi, S. & Patrono, C. (2002) Platelet activation in obese women: role of inflammation and oxidant stress. JAMA 288: 2008–2014.
35. Frame, L. T., Hart, R. W. & Leakey, J. E. (1998) Caloric restriction as a mechanism mediating resistance to environmental disease. Environ. Health Perspect. 106: 313–324.
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