1. BACKGROUND

Cancer is the most common fatal disease of childhood in the United States. Between ages 1 and 15, only accidents kill more children. Approximately 14/100,000 children develop cancer each year, or about 7500 children in the United States (1,2). This incidence rate indicates that about 1 in 500 children develop cancer before the age of 15. The common cancers of childhood are not those of later life; leukemia accounts for about one-third of childhood cancers and brain tumors about one-fifth. The other major cancers, in order of frequency, are lymphoma, neuroblastoma, Wilms’ tumor, soft tissue sarcoma, osteogenic sarcoma, and retinoblastoma (2). Since the early 1970s, the incidence of childhood cancer appears to be increasing slowly (1), but whether the observed increase reflects better diagnosis or real change is not known. The same time period has also seen a dramatic improvement in the survival of children with cancer with approx 70% of these children now alive 5 yr after diagnosis (2). However, some are left with long-term medical and cognitive problems.

Little is known about the etiology of cancers in children. The medical literature contained few epidemiologic studies of childhood cancer before the 1970s, but the extent of interest and investigation has increased dramatically since then. Many risk factors have been investigated, including genetic abnormalities and parental occupational exposures, in addition to aspects of diet that are the focus of this review.

The relationship between diet and childhood cancer has been studied little. In fact, nearly all the data discussed here come from 12 studies (see Table 1) (3–15). The possibility that a child’s diet or the mother’s diet during pregnancy can raise or diminish the risk of these rare cancers at first seems unlikely. The adult cancers most strongly linked with diet, such as stomach and colon, are believed to have latency periods of several decades. In contrast, cancers in children by definition have latencies of no more than 15 yr and often less than 5 yr. Furthermore, cancers of the digestive tract and of other sites linked to diet in adults rarely occur in children. Therefore, researchers first focused their search for causes on genetic predisposition and exposure to environmental toxins rather than diet.

The cancers of childhood, mainly leukemia, brain tumor, lymphoma, and sarcoma, occur relatively rarely in adulthood, and the etiologic hypotheses about these cancers

From: Preventive Nutrition: The Comprehensive Guide for Health Professionals, 2nd ed. Edited by: A. Bendich and R. J. Deckelbaum © Humana Press Inc., Totowa, NJ

3

4

Table 1 Studies of Childhood Cancer and Diet^a

5

(continued)

6

Table 1 (continued)

Infant’s/child’s Infant’s/child’s Authors and reference Child’s cured meat consumption fruit consumption vitamin supplement use

Preston-Martin et al., All cured meats, OR 2.3^c 1982 (3) Howe et al., 1989 (4) All cured meats, OR 1.1 Fruit juice, OR 0.2^c Vitamin supplement, no association

Vitamin C supplement, OR 0.9 Kuijten et al., 1990 (5) Bunin et al., 1993 (6) No fruit as infant, OR 4.3^c Multivitamin as infant, OR 0.7

Orange juice, apple juice, other fruit juice as infant, no association

Bunin et al., 1994 (7) Fruit, individual fruit juices Multivitamin as infant, as infant, no association no association McCredie et al., 1994 (8,9) Fruit as infant, OR 0.4 Vitamin supplement as infant, OR 0.9 Orange juice as infant, Vitamin syrup as infant, OR 0.5

OR 1.8 Apple juice as infant, OR 0.3 Sarasua and Savitz, Hot dogs, OR 2.1 Vitamin supplement, OR 0.4^c 1994 (10)^d Other individual cured meats,

ORs 0.6 and 1.4

Individual cured meats in absence of vitamin supplements, ORs 3.2–6.8^c

All cured meats, OR 0.7 Cordier et al., 1994 (11) Fresh fruit, OR 0.6 Vitamin supplement, OR 0.2^c Orange juice, OR 0.5 Preston-Martin et al., 1996 (12) (VISIT &BUY FROM  : WWW.DRUGSWELL.COM  &WWW.LEBANONWOW.COM  order now )
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^a For all foods, odds ratio presented is that for highest level of consumption. ^b OR: odds ratio. ^c Statistically significant. ^d Listed as two studies because separate analyses presented for brain tumors and acute lymphocytic leukemia (ALL). ^e Calculated from data presented in reference.

have generally not been dietary. Therefore, the literature on adult cancers adds only a limited amount to the discussion, but is considered where relevant.

Diet might act to alter cancer risk in children by mechanisms similar to and different from those proposed for adult cancers. Antioxidants such as vitamin C and -carotene may protect against various cancers by their ability to neutralize free radicals and thus prevent oxidative damage to DNA (16). Folic acid deficiency may encourage malignant transformation of normal cells by altering gene expression and weakening chromosomal structure (17). Exposure to N-nitroso compounds may initiate cancer through direct acting or metabolically activated carcinogens in this class of substances. Antioxidants and folic acid may act in fetuses and children through the same mechanisms as they are hypothesized to act in adults. Carcinogens may also act through the same mechanisms at all ages, but fetuses may be more susceptible to carcinogens, as suggested by animal studies of some N-nitroso compounds. Some substances might actually have the opposite effect in fetuses as in adults, as proposed for topoisomerase II inhibitors (see Subheading 4). Mechanisms unique to the embryo or fetus may also exist. An excess or deficiency of a dietary component could result in malformation of an organ or subtle cellular changes that increase the organ’s susceptibility to cancer. This type of altered development has been proposed as a mechanism leading to cancer in young women after prenatal DES exposure (18–20).

2. N-NITROSO COMPOUNDS

Most of the data on childhood cancer and diet come from studies of exposure to Nnitroso compounds (NOC) and risk of brain tumors. The overall category of N-nitroso compounds can be broken down into subgroups that include nitrosamines, nitrosamides, and nitrosoureas. N-nitroso compounds occur in our environment, as do substances that can combine to form these compounds. Nitrite, nitrogen oxides, and other nitrosating agents can react with nitrogen containing compounds such as amines, amides, and ureas to form N-nitroso compounds. Particularly relevant to the discussion of the relationship between diet and cancer are preformed N-nitroso compounds, nitrite, and nitrate, which can be reduced to nitrite in saliva.

Many N-nitroso compounds are potent mutagens and animal carcinogens. N-nitroso compounds have been found to be carcinogenic in a variety of tissues and organs in 40 animal species. Some N-nitroso compounds, when administered to pregnant animals, induce tumors in the offspring. Of particular relevance to childhood cancer is the fact that some nitrosoureas are potent nervous system carcinogens when given transplacentally (21).

Not only are N-nitroso compounds potent carcinogens, but also exposure to these compounds is widespread. Humans are exposed to N-nitroso compounds directly and to precursor compounds that can combine to form NOCs in the body. N-nitroso compounds have been detected in many common products including cigarette smoke, rubber, cured meats, cosmetics, alcoholic beverages, medications, pesticides, automobile interiors, water, air, and in some industrial settings (21–23). Almost all the data on the sources of N-nitroso compounds are on the occurrence of nitrosamines. Less is known about the distribution of other N-nitroso compounds, including the nitrosoureas that are transplacental nervous system carcinogens in animals.

Although N-nitroso compounds occur in the environment, most human exposure is thought to occur via endogenous synthesis. There is evidence that N-nitroso compounds

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 Chapter 1 / Diet and Childhood Cancer

can be synthesized in the stomach and elsewhere in the body (21). Cured meats, baked goods, and cereal contribute most of the nitrite (a NOC precursor) in the diet (22,24). For nitrates, which can be converted to nitrites, vegetables are the main dietary source (22,24).

The endogenous formation of N-nitroso compounds induces tumors in animals. When animals are fed N-nitroso precursors, for example, nitrite and an amine, the expected compound, in this case a nitrosamine, is produced in the stomach and tumors result as they do from feeding the preformed nitrosamine (21). There are substances that inhibit the formation of N-nitroso compounds from precursors in vivo, including vitamin C, vitamin E, selenium, and glutathione (21). In animals, these substances inhibit the formation of N-nitroso compounds from precursors and reduce the proportion of animals that develop tumors (25). In some studies, very large doses of vitamin C prevented 100% of tumors (25). In addition to inhibitors, accelerators of the nitrosation reaction are also known and include metal ions, thiocyanate, and certain carbonyl compounds (21).

Based on the animal data, particularly those concerning transplacental carcinogenesis, Preston-Martin et al. hypothesized that exposure to N-nitroso compounds during gestation increases the risk of brain tumors in children (3). Children whose mothers frequently ate foods containing N-nitroso compounds or nitrite were hypothesized to be at increased risk. The effect of nitrate-rich foods was more difficult to predict; vegetables contribute the majority of nitrates in the diet, but also contain vitamin C, an inhibitor of nitrosation. High intakes of vitamins C and E were hypothesized to decrease the risk because of their action as inhibitors of nitrosation reactions.

3. BRAIN TUMORS

Brain tumors are the second most common type of cancer among children in the United States, accounting for about 20% of these cancers. The annual incidence is approx 3/million children under the age of 15 and appears to have increased substantially since the early 1970s (1). A recent analysis suggests that the observed trend does not reflect a genuine increase, but rather a change in reporting and/or improved diagnosis (26). Some brain tumors occurring in children can be cured surgically, but others require a combination of surgery, radiation, and chemotherapy. With the use of multimodality therapy, survival from childhood brain tumors has improved to almost 50% (2), but survivors are often left with neurologic, cognitive, or endocrinologic problems.

Many different histologic types of brain tumor occur in childhood. The major categories are astrocytic glioma and medulloblastoma (sometimes referred to as primitive neuroectodermal tumor), which account for approx 50% and 20% of childhood brain tumors, respectively (27). Other types of glioma, ependymoma and oligodendroglioma, comprise another 10% of the total (27). The remaining brain tumors are soft tissue sarcomas, germ cell tumors, and tumors of unspecified type (27).

The patterns of incidence with age and gender differ among the histologic types (28). For example, astrocytic glioma affects boys and girls with equal frequency, but boys have a higher risk of medulloblastoma. The incidence of astrocytic glioma peaks between 4 and 8 yr of age compared to a peak before age three for medulloblastoma. These differences in demographic pattern suggest that the two major categories of childhood brain tumors might differ etiologically. On the other hand, the fact that all tumor types arise in the brain and, thus, share that environment, might imply a common etiology. Perhaps, some etiologic factors are common among different histologic types of brain tumors and others are specific to particular types.

In most epidemiologic investigations, childhood brain tumors have been studied together as a single entity. If risk factors differed by type of brain tumor, one would expect the studies of all types combined to mostly reflect risk factors for astrocytic glioma, the most common type. For this reason, studies of all types and astrocytic glioma are discussed together and the single study of medulloblastoma is considered separately.

4. LEUKEMIA

Leukemia accounts for about one-third of all cancer in children under age 15. In the United States, the annual incidence rate of leukemia in children is 4/100,000 with about 70% surviving at least 5 yr (1,2). Three-quarters of leukemias in children are classified as acute lymphocytic leukemia (ALL) and 15% as acute myeloid leukemia (AML). Other types of leukemia and leukemias not categorized as a specific type make up the remaining 10%. Similarly to the different types of brain tumors, different types of leukemia vary in patterns of incidence (42). ALL in children is more common in males than females and in whites than blacks, and peaks in incidence between ages 3 and 5. The incidence patterns for AML are quite different; male–female and white–black differences are slight and incidence is fairly constant throughout childhood. Very few data exist on any aspect of diet in relation to childhood leukemia.

A specific hypothesis regarding diet has been put forth for leukemia, particularly in infants (42). In the great majority of infant leukemias, the leukemia cells have abnormalities in band q23 of chromosome 11. Leukemias that occur after cancer treatment with epipodophyllotoxins, a class of chemotherapeutic agents, also have 11q23 abnormalities. Epipodophyllotoxins inhibit an enzyme called topoisomerase II, which is necessary for DNA replication. If epipodophyllotoxins inhibit topoisomerase II and increase the risk of leukemias with 11q23 abnormalities, perhaps other inhibitors of this enzyme also increase the risk of the same leukemias. Other inhibitors of topoisomerase II exist in nature, including certain flavonoids and medications (43,44). Flavonoids, substances found in plants, occur in the diet in fruits, vegetables, herbs, beans, wine, beer, and other plant derived foods (45). Medications that inhibit topoisomerase II include quinolones, which are used to treat urinary tract infections (46).

The specific hypothesis of Ross et al. regarding leukemia is that maternal exposure to topoisomerase II inhibitors during pregnancy increases the risk of leukemias with 11q23 abnormalities in infants (42). According to the hypothesis, children of mothers who frequently ate fruits, vegetables, beans, and other plant-derived foods would be at higher risk of leukemia. Paradoxically, these foods and flavonoids themselves have

Chapter 1 / Diet and Childhood Cancer

been associated with a decreased risk of some adult cancers (47). Perhaps, as Ross et al. speculate, flavonoids affect fetuses and adults differently. Fetuses are rapidly growing and have high rates of cell division and thus high levels of topoisomerase II, while adults have much lower rates of cell division and topoisomerase II activity. Ross et al. suggest that topoisomerase II inhibition may be detrimental in a rapidly growing fetus.

Ross et al. investigated their hypothesis in a preliminary study of leukemia from birth to 12 mo of age (15). Mothers of cases and controls who had participated in previous studies of leukemia were recontacted and asked about their intake of 26 food items. Mothers of 84 cases and 97 matched controls were interviewed. A priori, the following ten foods and beverages were considered to contain topoisomerase II inhibitors: beans, fresh vegetables, canned vegetables, fruits, soy, regular coffee, wine, black tea, green tea, and cocoa (as a beverage). Frequent intake of fresh vegetables and regular coffee was associated with increased risk. When total consumption of all ten inhibitor-containing foods was investigated, no association was observed. However, when the two subgroups of infant leukemia were analyzed separately, the results were quite different. For AML, increasing intake of foods containing topoisomerase II inhibitors was significantly associated with risk, with odds ratio of 9.8 for high consumption. Among the individual food items, beans, fresh vegetables, and fruit showed significant trends for AML. For the other subgroup, ALL, neither the inhibitor-containing foods as a group or any of the composite foods were significantly associated with risk. The authors recommend extreme caution in interpreting these results. Chance could explain the findings because of the small numbers of subjects in certain categories of intake and leukemia type. Selection bias is another possible explanation since only 84 of 303 eligible cases could be reached and interviewed for this preliminary study. However, these findings demonstrate the need to investigate the hypothesis further.

Two groups of investigators have examined the effects of a small number of dietary factors related to the N-nitroso hypothesis (10,13). Although animal data have not linked N-nitroso compounds with leukemia, the potency of these carcinogens and the possibility of enhanced potency through transplacental exposure suggested investigation. Peters et al. conducted a study in California of 232 children ages 0–10 with leukemia and the same number of controls (13). Sarasua and Savitz included all types of cancer before age 15 in their study and present analyses that compare the 56 cases of ALL to the 206 controls (10). In neither study was diet the major focus and thus, the amount of information collected on diet is limited. Peters et al. collected data on 11 food items and Sarasua and Savitz on five food items and on vitamin supplements.

The study by Peters et al. observed an increased risk associated with frequent consumption of hot dogs by the mother, father, and child. The risks were high, with relative risks of about five, which were significant for the father and child. The investigators also observed elevated risks for eating of other cured meats by the child, but not by the parents. When the diet and other factors were considered simultaneously, the father’s and the child’s frequent hot dog consumption remained strongly and significantly associated with increased risk.

In contrast to the findings of Peters et al., Sarasua and Savitz did not observe increased risk associated with the mother’s or child’s eating of hot dogs. However, for the child, when the effect of frequent cured meat consumption and not using vitamin supplements was analyzed, a threefold increased risk was observed for each of the cured meats, including hot dogs.

Peters et al. investigated another dietary item, citrus fruit, relevant to the N-nitroso hypothesis because of its concentration of vitamin C. Consumption of citrus fruit or juice by the child or the mother did not appear to influence risk.

A few foods not related to the N-nitroso hypothesis were also studied. Both studies included hamburgers among the food items in the questionnaire. In the larger study of Peters et al., no effect was observed, although Sarasua and Savitz’s smaller study observed a doubling of risk. Charbroiled meats did not affect risk of leukemia in either study. The increased risk associated with the child’s cola drinking (13) disappeared when adjusted for hot dog eating and other variables.

Another study with data relevant to the question of childhood leukemia and diet was conducted in Shanghai, China (14). In a case-control study with 309 cases and twice as many controls, use of cod liver oil for more than a year appeared to decrease the risk of both ALL and acute nonlymphocytic leukemia. Cod liver oil contains vitamins A and D.

The study of serum antioxidant levels cited in the brain tumor section also presented data on leukemia (35). Compared to controls, children with leukemia had lower serum levels of -carotene, retinol, selenium, and zinc. The interpretation is difficult, as the differences may reflect the effects of the leukemia itself rather than etiologic influences.

Knowledge of adult leukemia does not add much to this discussion. A case-control study of acute leukemia in Poland included questions on frequency of consumption of about 40 food items (48) and observed frequent drinking of milk and consumption of poultry to be associated with higher risk and frequent eating of vegetables with lower risk. To our knowledge, no other case-control or cohort study has investigated the relationship between diet and leukemia in adults. In an ecological study of data from 24 countries, total and lymphocytic leukemia incidence was significantly correlated with total calorie intake (49). Countries with high-caloric intake tended to have high leukemia incidence and those with low-caloric intake had a lower incidence. Findings from ecological studies can provide only indirect evidence, but the international correlation fits well with animal data that calorie or protein restriction reduces the incidence of leukemia (50).

The data on diet and childhood leukemia, although limited, suggest that further study may be productive. Any observed dietary association with childhood leukemia is worthy of pursuit, as we still know very little about the etiology of this disease. The preliminary results on foods containing topoisomerase II inhibitors are intriguing and deserving of further study. The findings concerning hot dogs and vitamins are consistent with the N-nitroso hypothesis, although the findings on citrus fruit do not fit. The association with hot dog consumption might also be consistent with risk factors of fat intake, total calories, infrequent vegetable consumption, and weight. Clearly, comprehensive studies of diet and childhood leukemia are required.

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A few studies of other childhood cancers have reported isolated findings related to diet. A small study of rhabdomyosarcoma observed an increased risk associated with the

Chapter 1 / Diet and Childhood Cancer

child’s eating of organ meats (51). In a much larger study designed to follow-up on this and other findings, investigators were unable to confirm the observation

(S. Grufferman, personal communication). A decreased risk of retinoblastoma was observed in relation to use of multivitamins by the mother during pregnancy (52).

6. VITAMIN K

The role of vitamin K has been studied in relation to its administration to newborns rather than as a component of diet. In many industrialized countries, newborns are routinely given vitamin K to prevent hemorrhagic disease, unexpected bleeding in previously healthy neonates. In 1990, Golding et al. reported an association between receiving vitamin K as a newborn and development of cancer before age 10 (53). The finding of an approximate doubling of risk arose unexpectedly in a nested case-control study of children born in 1970 in Great Britain. The results of a second study in Great Britain observed an increase in risk of similar magnitude for vitamin K administered intramuscularly, but not orally (54). The finding corroborated the first study as in 1970, the year of birth of the children in that study, vitamin K was almost always given intramuscularly. These two studies raised concern as newborns in many industrialized countries receive vitamin K routinely by intramuscular injection. Oral vitamin K can be given, but is less effective at preventing hemorrhagic disease. Swedish researchers studied 1.3 million infants born full term after uncomplicated delivery between 1973 and 1989 (55). By record linkage, these children were followed until 1992; approx 2350 children in the cohort developed cancer. No increase in risk of cancer overall or of leukemia was observed with exposure to intramuscular vitamin K. Similarly, a United States study did not observe cancer risk to be associated with vitamin K given to neonates (56). When the four studies are considered together, it seems unlikely that vitamin K given neonatally is a major cause of cancer during childhood.

7. CONCLUSION

Studies of the relationship between diet and risk of childhood cancer are few and most have focused on one hypothesis. Only the two most common cancers of childhood, leukemia and brain tumor, have been studied in any detail. Our knowledge of the role of diet in the etiologies of these cancers is meager. Nonetheless, the findings of the few studies suggest that diet does play a role in at least some childhood cancers. Future research will elucidate the particulars and extent of the role.

8. RECOMMENDATIONS

Maternal cured meat consumption has been fairly consistently associated with brain tumor risk in children, but whether the association is causal is unclear. Also, the frequency of cured meat consumption that was associated with higher risk varied greatly among the studies. For these reasons, a specific recommendation is not possible or appropriate. However, since cured meats are high in salt and fat, nutritional concerns other than the child’s cancer risk, such as keeping one’s fat and salt intake within recommendations, require that cured meats be eaten in no more than moderate quantities. Women eating cured meats several times a week or more might wish to reduce their intake during pregnancy.

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30. Ekelund H, Finnstrom O, Gunnarskog J, Kallen B, Larsson Y. Administration of vitamin K to newborn infants and childhood cancer. Br Med J 1993; 307:89–91.

31. Klebanoff MA, Read JS, Mills JL, Shiono PH. The risk of childhood cancer after neonatal exposure to vitamin K. N Engl J Med 1993; 329:905–908.

1. INTRODUCTION

This chapter will focus on lifestyle factors associated with cancers of the esophagus and stomach. Unlike such major cancers as prostate and breast, whose etiologies remain obscure at the present time, hindering primary prevention, cancers of the upper gastrointestinal tract offer well-defined intervention opportunities. Epidemiologic studies have clearly established the important role of alcohol, tobacco, and diet, and recent findings have documented the relation between infection with Helicobacter pylori and cancer of the stomach. These factors and their interactions will be discussed for cancers of each of these two sites, which together account for approx 35,000 new cases and 26,000 deaths annually in the United States (1).

2. CANCER OF THE ESOPHAGUS (VISIT &BUY FROM  : WWW.DRUGSWELL.COM  &WWW.LEBANONWOW.COM  order now )
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For many years, cancer of the esophagus in the United States, and in most areas throughout the world, was virtually synonymous with squamous cell carcinoma (2). Hence, most of the established risk factors for esophageal cancer are specific to this cell type, which comprised the vast majority of cases in studies of this cancer. Recent shifts in the histopathologic cell type have given rise to a rapid increase in the incidence of adenocarcinoma of the esophagus in the United States, particularly among white males (3). Because of the increasing importance of esophageal adenocarcinoma, a separate section will consider this entity, which may differ in etiology from squamous cell carcinoma.

3. CANCER OF THE STOMACH

A steady decline in gastric cancer has been apparent in many countries for the past several decades. The declining rates were first noted in the United States as early as 1930 (79) and have persisted throughout this century (1). Survival rates have not appreciably changed (1,80) therefore, the decline in deaths cannot be attributed to better treatment and prolonged survival, but to actual declines in incidence that are now well documented (81). This decline, believed to reflect changes in environmental factors, has been referred to as an “unplanned triumph” since the shifts did not result from active medical or public health intervention and are believed to result from large shifts in food processing and consumption (82). It should be noted that the increase in esophageal adenocarcinoma documented in the previous section does include an increase in adenocarcinomas of the gastroesophageal junction and gastric cardia.

4. RECOMMENDATIONS

Primary prevention of esophageal cancer obviously begins with prevention of tobacco use by teenagers and cessation among addicted adults. Use of nicotine patches and gum in conjuction with behavioral modification may improve the success rate for smokers attempting to quit. A reduction in tobacco use by teenagers has proven a persistent challenge because education programs are offset by well-funded, effective, targeted marketing by tobacco companies. The terms of the 1998 Tobacco Settlement have the potential to reduce if not eliminate these marketing approaches. Limiting alcohol consumption to moderate levels is particularly important in smokers, and physicians should actively counsel patients accordingly. Physician prompting and participation in smoking cessation efforts have proven effective.

Intake of fresh fruits and vegetables in the United States continues to fall short of the recommended “5-A-Day” (170). Increased consumption should continue to be promoted and benefits are expected to accrue in reduced rates of both of these upper digestive tract cancers as well as other epithelial tumors. Effective population-based approaches are important, and since dietary patterns are often established in childhood, promotion of healthy choices in school-based food service programs is an opportunity that should not be missed.

The current dietary recommendations of the American Cancer Society, the American Heart Association, and the National Cancer Institute are remarkably similar in direction, but differ in specificity. They are included for reference in Table 3.

The efficacy of vitamin/mineral supplements has not yet been established in clinical trials; however, in case-control and cohort studies the individuals in the highest level of intake of specific micronutrients often combine high dietary intake with supplements. With the obvious caution to avoid excessive intake, a multivitamin/mineral supplement, or specific antioxidant supplement may complement dietary intake, particularly among persons with excessive oxidative stress, such as smokers.

In the United States, the treatment and eradication of H. pylori is currently recom

38

Table 3 Dietary Recommendations of Selected Health Agencies

Chapter 2 / Prevention of Gastrointestinal Cancers

mended only for persons with gastric and duodenal ulcers, but not for persons with nonulcer dyspepsia (171). Although the spectrum of clinical outcomes associated with

H. pylori infection is wide ranging, from asymptomatic to gastric cancer, treatment and eradication of infection when possible seems prudent because the cofactors that predispose an infected individual to gastric cancer have not yet been established. This approach is currently followed in Europe.

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28. Ward MH, Lopez-Carillo L. Dietary factors and the risk of gastric cancer In Mexico City. Am J Epidemiol 1999; 149:925–932.

29. Tuyns AJ. Salt and gatrointestinal cancer. Nutr Cancer 1988; 11:229–232.

30. Correa P, Fontham E, Pickle LW, Chen V, Lin Y, Haenszel W. Dietary determinants of gastric cancer in South Louisiana inhabitants. J Natl Cancer Inst 1985; 75:645–654.

31. La Vecchia C, Negri E, DeCarli A, D’Avanzo B, Franceschi S. A case-control study of diet and gastric cancer in northern Italy. Int J Cancer 1987; 40:484–489.

32. Friedman GD, Parsonnet J. Salt intake and stomach cancer: some contrary evidence. Cancer Epid Biomarkers Prev 1992; 1:607–608.

33. Bogovski P, Bogovski S. Animal species in which N-nitroso compounds induce cancer. Int J Cancer 1981; 27:471–474.

34. Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gatric cancer epidemiology. Lancet 1975; 11:58–60.

35. Ohshima H, Bartsch H. Quantitative estimation of endogenous nitrosation in humans by monitoring N-nitroproline excreted in the urine. Cancer Res 1981; 41:3658–3662.

36. Mirvish SS, Gandjean AC, Moller H, Fiki S, Mayard T, Jones L, et al. N-nitrosoproline excretion by rural Nebraskans drinking water of varied nitrate content. Cancer Epid Biomarkers Prev 1992; 1:455–461.

37. Moller H, Landt J, Pederson E, Jenson P, Autrup H, Jenson OM. Endogenous nitrosation in relation to nitrate exposure from drinking water and diet in a Danish rural population. Cancer Res 1989; 49:3117–3121.

38. Sierra R, Chinnock A, Ohshima H, Pignatelli B, Malaveille C, Gamboa C, et al. In vivo nitrosoproline formation and other risk factors in Costa Rican children from high- and low-risk areas for gastric cancer. Cancer Epid Biomarkers Prev 1993; 2:563–568.

39. Risch HA, Jain M, Choi N, Fodor JG, Pfeiffer CJ, Howe GR, et al. Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985; 122:947–959.

40. Chyou PH, Nomura AMY, Hankin J, Stemmermann GN. A case-control study of diet and stomach cancer. Cancer Res 1990; 50:7501–7504.

41. Buiatti E, Palli D, DeCarli A, Amadori D, Avellini C, Bianchi S, et al. A case-control study of gastric cancer and diet in Italy II. Association with nutrients. Int J Cancer 1990; 45:896–901.

42. Buiatti E, Palli D, Bianchi S, DeCarli A, Amadori D, Avellini C, et al. A case-control study of gastric cancer and diet in Italy III. Risk patterns by histologic type. Int J Cancer 1991; 48:369–374.

43. Hansson L-E, Nyren O, Bergström R, Wolk A, Lindgren A, Baron J, et al. Nutrients and gatric cancer risk. A population-based case-control study in Sweden. Int J Cancer 1994; 57:638–644.

44. Gonzales CA, Riboli E, Badosa J, Batiste E, Cardona T, Pita S, et al. Nutritional factors and gastric cancer in Spain. Am J Epidemiol 1994; 139:466–473.

45. Meinsma I. Nutrition and cancer. Voeding 1964; 25:357–365. (Cited in Bjelke, 1974)

46. Higginson J. Etiological gasctors in gastrointestinal cancer in man. J Natl Cancer Inst 1966; 37:527–545.

47. Haenszel W, Kurihara M, Segi M, Lee RK. Stomach cancer among Japanese in Hawaii. J Natl Cancer Inst 1972; 49:969–988.

48. Bjelke E. Epidemiologic studies of cancer of the stomach, colon and rectum. Scand J Gatroenterol 1974; 9:Suppl 31.

49. Haenszel W, Kurihara M, Locke FB, Shimuzu K, Segi M. Stomach cancer in Japan. J Natl Cancer Inst 1976; 56:265–274.

50. Trichopoulos D, Ouranos G, Day NE, Tzonou A, Manousos O, Papadimitriou CH, Trichopoulo A. Diet and cancer of the stomach: a case-control study in Greece. Int J Cancer 1985; 36:291–297.

51. Jedrychowski W, Wahrendorf J, Popiela T, Rachtan J. A case-control study of dietary factors and stomach cancer risk in Poland. Int J Cancer 1986; 37:837–842.

52. La Vecchia C, Negri E, DeCarli A, D’Avanzo B, Franceschi S. A case-control study of diet and gastric cancer in norther Italy. Int J Cancer 1987; 40:484–489.

53. You WC, Blot WJ, Chang YS, Ershow AG, Yang ZT, An Q, et al. Diet and high risk of stomach cancer in Shandong, China. Cancer Res 1988; 48:3518–3523.

54. Buiatti E, Palli D, DeCarli A, Amadori D, Avellini C, Biserni R, et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer 1989; 44:611–616.

Chapter 2 / Prevention of Gastrointestinal Cancers

1. Graham S, Haughey B, Marshall J, Brasure J, Zielezny M, Freudenheim J, et al. Diet in the epidemiology of gastric cancer. Nutr Cancer 1990; 13:19–34.

2. Wu-Williams AH, Yu M C, Mack TM. Life-style, workplace, and stomach cancer by subsite in young men of Los Angeles County. Cancer Res 1990; 50:2569–2576.

3. Negri E, LaVecchia C, D’Avanzo B, Gentile A, Boyle P, Parazzini F. Vegetable and fruit consumption and cancer risk. Int J Cancer 1991; 48:350–354.

4. Boeing H, Frentzel-Beyne R, Berger M, Berndt V, Gores W, Korner M, et al. Case-control study on stomach cancer in Germany. Int J Cancer 1991; 47:858–864.

5. Gonzalez CA, Sanz JM, Marcos G, Pita S, Brullet E, Saigi E, et al. Dietary factors and stomach cancer in Spain: A multicenter case-control study. Int J Cancer 1991; 49:513–519.

6. Hoshiyama Y, Sasabe T. A case-control study of single and multiple stomach cancers in Saitama Prefecture, Japan. Jpn J Cancer Res 1992; 83:937–943.

7. LaVecchia C, Ferreroni M, D’Avanzo B, Di Carli A, Francheschi S. Selected micronutrient intake and the risk of gastric cancer. Cancer Epid Biomarkers Prev 1994; 3:393–398.

8. Hansson L-E, Nyren O, Bergström R, Wolk A, Lindgren A, Baron J, Adami H-O. Diet and risk of gastric cancer. A population-based case-control study in Sweden. Int J Cancer 1993; 55:181–189.

9. Lopez-Carillo L, Avila MH, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: a case-control study. Am J Epidemiol 1994; 139:263–271.

10. Basu TK, Schorah CJ. Vitamin C reserves and requirements in health and disease. In: Vitamin C in Health and Disease. AVI, West Port, CT, 1982, pp. 62–92.

11. Stähelin HB, Gey KF, Eichholzer M, Lüdin E, Bernasconi F, Thurneysen J, et al. Plasma antioxidant vitamin and subsequent cancer mortality in the 12 year follow-up of the prospective Basel Study. Am J Epidemiol 1991; 133:766–775.

12. Haenszel W, Corra P, López A, Cuello C, Zarama G, Zavala D, et al. Serum micronutrient levels in relation to gastric pathology. Int J Cancer 1985; 36:43–48.

13. Kabuto M, Imai H, Yonezawa C, Nerüshi K, Akiba S, Kato H, et al. Prediagnostic serum selenium and zinc levels and subsequent risk of lung and stomach cancer in Japan. Cancer Epidemiol Biomarkers Prev 1994; 3:465–469.

14. Serdula MK, Coates RJ, Byers T, Simoes E, Mokdad AH, Subar AF. Fruit and vegetable intake among adults in 16 states: Results of a brief telephone survey. Am J Public Health 1995; 85:236–239.

15. Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994; 12(1):1–22.

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Cancer of the colon and rectum is the second most common cause of cancer mortality in Westernized countries (1,2). Incidence rates vary approx 20-fold around the world (1,2). The international differences, migrant data, and recent rapid changes in incidence rates in Italy, Japan, urban China, and Male Polynesians in Hawaii (1,2) show that this cancer is highly sensitive to changes in diet and other aspects of environment. Diet appears to have a particularly strong association with occurrence of this cancer (1–3) and thus offers promise for intervention. Furthermore, mortality from colon cancer in the United States has not changed substantially over the past 50 yr (4) suggesting that prevention may offer the best opportunity to control the disease.

In this chapter on diet and nutrition in the etiology and primary prevention of colon cancer, factors associated with either increased or decreased risk of this disease are reviewed. Both older, well-established (fat, meat, fiber, vegetables, and fruit) and newer, intriguing, but less well-established hypothesized associations are addressed (sucrose, calcium, vitamin D, milk products, antioxidants and antioxidant-enzyme-associated micronutrients, folate, tea). The former are covered first, but because they are reviewed extensively elsewhere (1–2,5), are summarized in less detail than the latter. That the newer hypotheses receive more space in the review should not be construed as a suggestion that they are thought more likely to be causal. Alcohol, which is reviewed extensively elsewhere (1,5), is not reviewed except in context with the folate–colon cancer association. Likewise, for a review of energy balance, including total energy intake and physical activity, the reader is referred to refs. 1 and 5.

2. FAT AND MEAT

The hypothesis that dietary meat and/or fat increases risk of colon cancer has been one of the dominant hypotheses related to colon carcinogenesis for the past generation. The observation that higher colon cancer mortality rates occurred in countries where fat and meat consumption was higher led to the hypothesis that these food items contributed to an individual’s risk of developing colon cancer and was a stimulus for the current intense interest in dietary intake in most analytic studies of the etiology of colon cancer (3,6–8).

From: Preventive Nutrition: The Comprehensive Guide for Health Professionals, 2nd ed. Edited by: A. Bendich and R. J. Deckelbaum © Humana Press Inc., Totowa, NJ

47

Highly plausible explanatory hypotheses have been developed in support of a causal relationship between meat and fat intake and colon cancer (see Table 1) and the data from animal and metabolic studies in support of these hypotheses have been substantial. The oldest hypothesis asserts that fat intake increases bile acid production, ultimately increasing the exposure of the bowel mucosa to the toxic, trophic, and tumor or cancer-promoting effects of bile acids (6). High-fat diets increase excretion of bile acids in both animals (9,10) and humans (9,11). Bile acids have been shown to damage DNA (12). In animals, bile acids have toxic effects on colon epithelial cells, resulting in compensatory colonic epithelial cell proliferation (13) and promotion of tumorigenesis (14,15). Also in animals, a high intake of saturated (16,17) and unsaturated fat (17,18) has increased the incidence of chemically induced colon cancer [although not entirely consistently (19)]. In metabolic epidemiologic studies, increased fecal concentrations of bile acids have been found in populations with higher rates of colon cancer (9,20), as well as in patients with colon polyps (21) or colon cancer (22,23) [again, not entirely consistently (24)]. In animals, the tumor-enhancing effects of bile acids are increased after enzymatic modification by intestinal bacteria (25). Among humans, the capacity of colonic flora to transform bile acids into potential carcinogens has been found to be greater in populations with high rates of colon cancer and among meat-eating populations than in vegetarian populations (9,26). Furthermore, this capacity is reduced when the intake of beef fat is reduced (26,27).

A more recent hypothesis is the cooked-food hypothesis (28), which proposes that the association with fat is misleading, at least in part. High-fat diets contain greater amounts of carcinogenic heterocyclic amines (from meat proteins) (29) and promoters as a consequence of cooking at high temperature (cooking in fat produces higher temperatures than cooking in water) (28). Thus, the argument goes, the meat hypothesis is really the high temperature:high carcinogens and promoters/low temperature:low carcinogens and promoters hypothesis. The two explanatory hypotheses are not incompatible and, if anything, enhance the plausibility of the meat/fat–colon cancer association.

A third and very recent hypothesis is that a high consumption of meat, particularly red meat, may increase fecal concentrations of iron, which catalyzes oxidative reactions, leading to increased lipid peroxidation and oxidative DNA damage, and, as described in more detail in Subheading 9., to increased risk for colon cancer (30). Also as described in Subheading 9., high-fat consumption has been associated with increased levels of oxidative damage.

Finally, in a recent, small metabolic study, meat intake, especially red meat intake, was found to be associated with increased production of N-nitroso compounds and precursors (31). G to A transitions in the gene K-ras occur in colorectal cancer and are characteristic of the effects of alkylating agents such as N-nitroso compounds (31).

Of at least 40 analytic epidemiologic studies investigating the meat–colon cancer association (see ref. 1 for a review of the earliest 23; for example, see refs. 32–42; more recent studies include refs. (43–59), 23 found a direct association (for example, refs. 33, 34, 37–39, and 44–47, 49–54, 59), one an inverse association (40), and 17, no definite association (for example, refs. 35, 41–43, 48, 55–58). The only study to find an inverse association was a prospective mortality study in Japan (40), a society generally at low risk for colon cancer. Other studies have found inverse associations with poultry or fish (for example, refs. 51, 52, 55, 57, 59). A second prospective mortality study, this one in Seventh Day Adventists (41), reported a null association; and a third, a small cohort in

Chapter 3 / Diet and Colon Cancer

Table 1 Potential Mechanisms of Increased Risk of Colon Cancer with High Intakes of Meat or Fat^a

Fat increases bile acid production Bile acids damage DNA Bile acids are toxic to colon cells resulting in compensatory colonic epithelial cell

proliferation Bile acids in meat eaters vs in vegetarians more readily transformed into potential

carcinogens High-fat intake associated with increased oxidative damage Meat increases fecal iron, which catalyzes oxidative reactions, leading to increased

oxidative damage Meat cooked at high temperatures contains higher amounts of carcinogenic heterocyclic amines Red-meat intake increases endogenous production of potentially mutatgenic N-nitroso compounds

^a Potential mechanisms may not be mutually exclusive, and may be additive or synergistic.

white males (45), found a direct association. Of five prospective studies of incident colorectal cancer, one, the Nurses’ Health Study (39), reported a direct association; a second, the Iowa Womens’ Health Study, using the same food frequency questionnaire as the Nurses’ study, reported a null association (42); a third, the Norwegian National Health Screening Service cohort with 143 cases found a null association for total meats, but a direct association for sausage limited to women (43); a fourth, in Seventh Day Adventists, in contradistinction to the earlier mortality study, found a direct association (44); and the fifth, a Finnish cohort study, found direct associations with smoked, salted fish, cured meat, and meats with N-nitroso compounds (54).

Of at least 26 studies investigating the fat–colon cancer association (see ref. 1 for a review of the earliest 18; for examples, see refs. 33, 34, 37–39, 42, and 60; more recent studies include refs. (43, 52, 56, 57, 61–64), 12 found a direct association (for example, refs. 33, 34, 37–39, and 56, 64), 2 an inverse association (60,63), and 15, no definite association (for example, refs. 35, 42, and 43, 48, 52, 56, 57, 63, 64). The only studies to find an overall inverse association were a prospective study of Hawaiians of Japanese descent (60), and a case-control study of Montreal francophones that found nonsignificant odds ratios (ORs) of 0.78 and 0.71 for total and saturated fats, respectively (63). However, another study found a statistically significant inverse association (OR 0.6) with the ratio of polyunsaturated to saturated fatty acids (52). Only four prospective studies have examined the fat–colon cancer association; one, a mortality study in Seventh Day Adventists (41), reported a null association; the second, the Nurses’ Health Study (39), reported a direct association; the third, the Iowa Womens’ Health Study (42), using the same dietary assessment instrument, reported a null association; and the fourth, the Norwegian National Health Screening Service cohort study (43), found a null association for total fat and for various types of fat.

Of interest is that the Nurses’ Health Study (39), the Iowa Womens’ Health Study (42), and one case-control study (38) used essentially the same dietary assessment instrument. The Nurses’ Health Study, and the Iowa Womens’ Health Study, are both extant large prospective studies limited to women that used similar statistical techniques in their reported analyses. The Nurses’ Health Study, however, was limited to women who were 30–55-yr-old registered nurses living in 11 large states in the United States, whereas the Iowa Womens’ Health Study was limited to 55–69-yr-old women living in a single state, but of any employment status or occupation. The case-control study, a 1989 population-based study in Los Angeles, CA limited to 45–69-yr-old men and women, found null associations for meat and fat (as did the Iowa Womens’ Health Study). Although these three studies differed on statistical significance, directions of associations with meat, types of meat, and fat were fairly consistent across studies. Of further note is that the Iowa Womens’ Health Study, the Nurses’ Health Study, and several (for example, refs. 34, 36, 51, 52, 55, 57, 59), but not all (for example, ref. 35) other studies that have investigated different types of meats in relation to colon cancer reported associations that involved higher fat meats (red meats, processed meats, and so on) were consistent with increased risk, whereas associations that involved fish, other seafoods, or skinless poultry were consistent with decreased risk.

Although associations between fat and meat and colon cancer have now been investigated in over 40 analytic epidemiologic studies, and although direct associations were found in approximately two-thirds of these studies, findings are too inconsistent to establish causal relationships. Furthermore, as pointed out by Willett et al. (39,65), the interpretation of many studies is hampered by the common finding of a direct association between total energy intake and colon cancer risk (for examples, see refs. 66–70), thus raising uncertainty as to whether it is the total amount of food consumed or the fat or meat components of the diet that is etiologically important. Differences in the findings of the many studies may be because of differences in study designs, populations [for a good illustration, see Whittemore et al. (71)], dietary assessment methodologies, and analysis procedures (including energy adjustment techniques and groupings of meat and fat); and different ranges of dietary intakes, cooking practices, genotypic or phenotypic susceptibility, and molecular characteristics (implying possible differences in etiologies) of the cancers across populations. Null associations in many studies may be related to dietary or cooking method homogeneity within populations, the lack of accuracy of currently available dietary assessment instruments, and mix of genetically susceptible individuals or tumors of given molecular characteristics/etiologies.

For example, some, but not all, studies that have examined the association of meat doneness or method of preparation have found a stronger risk with cooking at higher temperatures or to greater degrees of doneness, as surrogates of heterocyclic amine exposure (2). Even more recently, some studies have found even stronger associations with indicators of heterocyclic amine exposure from cooking meat with rapid activity of some enzymes that metabolize heterocyclic amines (48,50,53,72,73). In these studies N-acetyltransferase activity was indicated by either phenotyping using model compounds or genotyping for polymorphisms of NAT1 and NAT2. One study suggested that risk from beef was more associated with tumors that were p53 negative (49), but a second study found no associations with various groupings of meat regardless of the p53 status of the tumors (56).

Opposite findings within many studies for higher fat meats (increased risk) vs fish or seafoods (decreased risk) may have etiologic implications and suggest the need to investigate various meat groupings more vigorously. For example, if the mechanism of the hypothesized meat/colon cancer relationship is more a matter of low-fat meats vs

Chapter 3 / Diet and Colon Cancer

high-fat meats, then the bile acid explanatory hypothesis may be more tenable than the cooked-meat hypothesis. Alternative explanations, however, include other unidentified or accounted for healthy behaviors associated with low-fat meat consumption, potential protective effects of omega-3 fatty acids in seafoods [for example, omega-3 fatty acids have reduced colonic epithelial cell proliferation in a small clinical trial in humans (74)], and different cooking methods associated with red meats vs seafoods.

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The hypothesis that fiber decreases the risk of colon cancer, has, in addition to the fat hypothesis, been one of the dominant hypotheses related to colon carcinogenesis for over a quarter of a century. The idea was first proposed by Burkitt in 1969 based on his clinical observations that colon cancer appeared to be rare in Africans whose diet was high in unrefined foods (75). As reviewed elsewhere (76), mechanistic hypotheses (see Table 2) include that fiber, which comes primarily from plant foods:

1. Increases stool bulk, diluting the opportunity for fecal mutagens to contact the colon mucosa;

2. Decreases stool transit time, thus providing less time for fecal mutagens to contact the colon mucosa;

3. Binds or dilutes bile acids, thereby reducing their toxic, trophic, and promoting effects (see discussion of bile acids in Subheading 2.);

4. Ferments to volatile fatty acids that may be anticarcinogenic;

5. Ferments to volatile fatty acids that decrease pH, thereby reducing the conversion of primary to secondary bile acids, and reducing the solubility of free bile acids, thus decreasing their availability for cocarcinogenic activity;

6. Ferments, thus leading to the release of bound calcium (see implications for this in Subheading 6.);

7. Binds carcinogens; and

8. Induces different patterns of colonic bacteria, thus influencing types and degrees of metabolic reactions.

It is becoming more apparent, however, that regarding dietary fiber as a single entity may be misleading and oversimplifying the fiber–colon cancer association. Fiber classifications that may be important etiologically include nonstarch polysaccharides (cellulose, hemicelluloses, pectin, gums, mucilages) vs nonpolysaccharides (lignin), water soluble (pectin, gums, mucilages, and some hemicelluloses) vs water insoluble (cellulose, lignin, and most hemicelluloses), fermentable vs nonfermentable, cereal vs vegetable, and so on. For example, cellulose and wheat bran have been shown to decrease fecal bile acid concentrations, whereas oat and corn bran have been shown to increase concentrations. Insoluble fiber tends to increase fecal bulk and decrease transit time, whereas soluble fiber has less effect. (Cellulose is found primarily in root and leafy green vegetables and legumes; hemicellulose primarily in cereal brans; pectin in fruit, and gums in legumes and oats.)

Furthermore, results of animal studies involving fiber feeding and colon cancer have been mixed (76–78). Part of the inconsistency may be caused by feeding different types of fiber. Wheat bran, although not in every study, has been the fiber most consistently providing an apparent protective effect. Results of studies of oat bran, corn bran, and pectin have been more mixed.

Table 2 Potential Colon Anticarcinogenic Mechanisms of Dietary Fiber^a

Increases stool bulk, diluting fecal mutagens Decreases stool transit time, decreasing fecal mutagen contact time Binds or dilutes bile acids, reducing their mutagenic and cytotoxic effects Binds or dilutes carcinogens Ferments

to volatile fatty acids that are potentially anticarcinogenic

to volatile fatty acids that decrease pH that reduce conversion of primary to more carcinogenic secondary bile acids reduce solubility, thus carcinogenic activity, of free bile acids

leading to release of bound calcium which may bind bile acids Induces different patterns of colonic bacteria, thus influencing type and degree of relevant metabolic reactions

^a Potential mechanisms may not be mutually exclusive, and may be additive or synergistic.

The results of observational epidemiologic studies of fiber and colon cancer have been mixed (43,57,63,66,76,79–85), but generally supportive of the fiber–colon cancer hypothesis. Of 19 case-control studies assessing fiber intake as a specific dietary constituent, eight provided strong support for a protective effect, five provided moderate support, four no support, and two suggested an increased risk with increased fiber intake. A meta-analysis of 13 case-control studies (using original data) (86), found an approximate halving of risk for those in the highest quintile of fiber intake compared to those in the lowest quintile ( p for trend 0.0001). The results of four prospective cohort studies in women (43,57,83,87) have not provided strong support for dietary fiber, on the whole, as being protective against colon cancer. In the Nurses Health Study (83), total dietary fiber, vegetable fiber, and cereal fiber, were not associated with risk.

In the Iowa Women’s Health Study (87), total dietary fiber was not associated with risk, although the relative risk for cancer of the distal colon was 0.66 (95% CI 0.34–1.29) for the highest quartile compared to the lowest, but there was no suggestion of a dose-response. In the Norwegian National Health Screening Service cohort, there was no apparent association of fiber and risk of colon cancer (43). In a mammography clinics cohort in New York and Florida (57), the relative risk was 1.5, but was not statistically significant. Two recent case-control studies had the capacity to estimate intakes of a wider variety of types of fiber. In one, a large hospital-based case-control study in Italy (79), inverse, but not statistically significant, associations were found for total fiber (nonstarch polysaccharides), soluble noncellulose polysaccharides, total insoluble fiber, cellulose, insoluble noncellulose polysaccharides, lignin, vegetable fiber, and fruit fiber, but not for cereal fiber. A large population-based case-control study in a racially diverse population in Hawaii (84), found evidence for decreased risk in association with dietary fiber, nonstarch polysaccharides, soluble fiber, insoluble fiber, cellulose, and noncellulose polysaccharides, but it appeared that these associations were all primarily caused by fiber from vegetable sources. There was also evidence to suggest that there was an association of vegetable fiber independent of other potential mechanisms of vegetables as potential reducers of risk.

On the whole, then, the idea that at least some types of dietary fiber may afford protection against colon cancer is highly plausible, and the animal experimental and human observational literature is generally supportive of the hypothesis. Much work needs to

Chapter 3 / Diet and Colon Cancer

be done to: (1) sort out which type(s) of fiber, if any, are protective in animals; (2) include valid estimates of intake of different fiber types in observational epidemiologic studies; and (3) conduct fiber feeding trials in humans.

4. VEGETABLES AND FRUIT

As reviewed more extensively elsewhere (76), vegetables and fruit contain a myriad of potentially anticarcinogenic compounds, and as a food group, have been more consistently associated with a reduced risk of colon cancer than any other dietary factor. Potential anticarcinogenic agents in plants (see Table 3) include fiber (reviewed in Subheading 3.), antioxidants and antioxidant enzyme-associated micronutrients (reviewed in Subheading 9.), and folate (reviewed in Subheading 10.). Other potential anticarcinogenic compounds for which there has of yet been little study (including no clinical trials) in humans include: dithiolthiones, glucosinolates and indoles, isothiocyanates and thiocyanates, coumarins, flavonoids, phenols, protease inhibitors, plant sterols, isoflavones, saponins, inositol hexaphosphate, allium compounds, and limonene.

Plant potential anticarcinogenic compounds, including the lesser studied ones, have both complementary and overlapping mechanisms of action, including the induction of detoxification enzymes, inhibition of nitrosamine formation, provision of substrate for formation of antineoplastic agents, dilution and binding of carcinogens in the digestive tract, alteration of hormone metabolism, antioxidant effects, and others. Dithiolthiones are present in cruciferous vegetables; when administered to animals, increase levels of glutathione and increase activities of glutathione reductase, glutathione transferase, quinone reductase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase; and are thought to protect against cancer by blocking the reaction of electrophilic carcinogens with cellular macromolecules (the mechanism probably depends on the induction of glutathione and the related conjugation enzymes) (76,88,89). Glucosinolates and indoles are both present in cruciferous vegetables, and some of these compounds increase microsomal mixed-function oxidase activity, which can lead to either activation or detoxification of carcinogenic compounds, the aggregate effect of which appears to be anticarcinogenic (76,90). Indoles have been found to protect against a variety of tumors in animals (76). Isothiocyanates and thiocyanates are present in cruciferous vegetables; inhibit DNA methylation; induce Phase II xenobioticmetabolizing enzymes such as glutathione S-transferase; and have been shown to be inhibitors of both early and late stages of carcinogenesis in animals (76,89). Coumarins are found in vegetables and citrus fruits; induce glutathione S-transferase activity; and have inhibited tumor formation in animals (75,88). Flavonoids (for example, quercetin and others) are found in most vegetables and fruits; have antioxidant properties; influence mixed-function oxidase activity; and have produced mixed results in animal anti-carcinogenesis experiments (76). Phenols are found in a variety of vegetables and fruits; some are also classified as antioxidants, flavonoids, or coumarins, others are not; induce detoxification enzymes (Phase II conjugation reactions); some inhibit N-nitrosation reactions; and have been found to decrease tumors in animals (91). Protease inhibitors are widely distributed in plants, but are particularly abundant in seeds, legumes, potatoes, and sweet corn; competitively inhibit proteases by forming complexes that block or otherwise affect their catalytic sites; and reduce the occurrence of tumors in animals (76,89,92). Plant sterols are found in vegetables; pass through the gastrointestinal tract