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15 Inhibitors of Carcinogenesis In recent years, a number of foods and constituents of foods have been studied for their inhibitory effects on carcinogenesis. Results from both epidemiological and experimental studies have indicated that some of the substances studied do have inhibitory effects, but the mechanisms are not yet clear. This chapter contains a review of the most conclusive data pertain- ing to the inhibitory effects of nonnutritive constituents of the diet. EPIDEMIOLOGICAL STUDIES Epidemiological studies have produced data suggesting that certain substances in foods may protect against the development of cancer. A substantial number of these studies have demonstrated an inverse re- lationship between consumption of vegetables and risk of cancer, es- pecially cancer of the gastrointestinal tract. Vegetables contain nutritive constituents with inhibitory capacities (as discussed in Section A and Chapter 9) as well as nonnutritive inhibitors, which are described in this chapter. The epidemiological data are not sufficient to permit a definition of the individual roles played by each of the several putative inhibitors that may be present in the same food. Never- theless, the data are of considerable interest even though the mechanism of inhibition is unclear. In one study of stomach cancer, Graham et al. (1972) found that con- sumption of raw vegetables, including Cole slew and red cabbage, was higher among controls than among cases. In a study of Hawaiian Japanese, Haenszel _ al. (1972) reported lower risk of stomach cancer for con- sumers of several Western vegetables, many of which are eaten raw. In a corresponding study in Japan, the same investigators reported a lower risk of stomach cancer for consumers of lettuce and celery (Haenszel et _., 1976~. In case-control studies conducted in Norway and in the United States (Minnesota), Bjelke (1978) also demonstrated an inverse relationship between incidence of stomach cancer and the indices for consumption of vegetables, especially among younger patients and women. He also reported preliminary findings from a prospective cohort study, showing a reduced risk of stomach cancer for consumers of large amounts of vegetables in Norway, but not in the United States. In Japan, Hirayama (1977) found that the risk for stomach cancer was lower for nonsmokers who ate green and yellow vegetables than for nonsmokers who did not eat these vegetables. 358 15-1

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Inhibitors of Carcinogenesis 359 Much of the epidemiological evidence pertains to cancer of the large bowel. Modan _ al. (1975) compared cases of colon and rectal cancer with both hospital and neighborhood controls and found an inverse associ- ation between colon cancer (but not for rectal cancer) and the frequent consumption of fiber-containing foods, including cabbage. Other inverse associations between consumption of fiber-containing foods and colon cancer (see Chapter 8) could also reflect different intakes of crucif- erous vegetables. Graham et al. (1978) reported that a decreased risk for colon cancer was associated with frequent ingestion of raw vegeta- bles, especially cabbage, Brussels sprouts, and broccoli, in a case- control study conducted in New York State. Similar but less impressive findings were obtained for rectal cancer. Haenszel _ al. (1980) found an inverse association for cabbage con- sumption in a case-control study of colorectal cancer in Japan, but not in Hawaii (Haenszel et al., 1973~. In the previously cited, ongoing cohort study in Minnesota and Norway, Bjelke (1978) noted that the risk for colorectal cancer is associated inversely with an index of vegetable consumption in Minnesota, but not in Norway. This result paralleled his earlier finding that the intake of vegetables, particularly cabbage, by colorectal cancer cases was less than for controls in Minnesota. EXPERIMENTAL STUDIES As discussed in Chapters 8, 9, and 10, certain vitamins, minerals, and fiber have been found to inhibit some forms of carcinogenesis. Dur- ing the past decade, studies have shown that foods also contain nonnutri- tive organic compounds that are also inhibitors of carcinogenesis. These compounds fall into a category frequently referred to as "secondary plant constituents." Among these constituents are phenols, indoles, aromatic isothiocyanates, flavones, protease inhibitors, and the plant sterol 6-sitosterol, which are discussed below along with related studies of the effects of individual foods. Effects of Selected Chemicals l The administration of selected chemicals in this category has been shown to inhibit both initiation and promotion of chemically induced neoplasia in virtually all organs of laboratory animals. As will become apparent in subsequent discussions, much remains to be learned about these numerous and virtually omnipresent dietary constituents, including their possible adverse as well as beneficial effects. The mechanisms by which these compounds prevent neoplasia is incom- pletely understood. Some inhibitors, so-called "blocking agents," exert their effects when administered before and during exposure to carcinogens. Others act during the promotion phase of carcinogenesis, and still others 15-2

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360 DIET, NUTRITION, AND CANCER inhibit only when given following exposures to inhibitors and promoters from other external sources. Finally, some inhibitors are effective at more than one point during the process of carcinogenesis. Of the in- hibitors identified thus far, the largest number falls into the category of blocking agents, appearing to act by preventing carcinogens or their metabolites from reaching or reacting with critical target sites. In many instances, they alter the activity of enzyme systems that metabolize carcinogenic agents (Wattenberg, 1981a). A second general form of inhibition is particularly relevant to pro- motion. The inhibitor is assumed either to suppress free radical forma- tion resulting from exposure to tumor promoters or to trap these radi- cals. Protease inhibitors and phenolic antioxidants have been postulated to inhibit neoplasia in this manner. The fact that a compound inhibits chemically induced carcinogenesis in laboratory animals should not be interpreted as indicating that an increased intake of the substance is desirable for humans. Knowledge of possible adverse effects of these compounds is incomplete (see discussion at the end of this chapter). Phenols. Two categories of phenolic inhibitors of carcinogenesis are found in food. One is synthetic and the other occurs naturally. The synthetic antioxidant, butylated hydroxyanisole (BHA) is a widely used food additive and has been extensively studied for its capacity to in- hibit carcinogens induced neoplasia (Wattenberg, 1978~. Table 15-1 lists experiments in which BHA has been shown to have inhibitory effects. In these studies, BHA was administered before and/or during exposure to the carcinogen. BHA has also been shown to inhibit host-mediated mutagenesis resulting from exposure to hycanthone, metrifonate, praziquantel, and metronidazole (Batzinger _ al., 1978~. Slaga (1981) reported that BHA inhibited tumor promotion in the mouse skin when administered after the carcinogen. Studies of the mechanism by which BHA inhibits chemically induced carcinogenesis have shown that this phenolic compound produces a co- ordinated enzyme response that may be interpreted as causing a greater rate of detoxification (Wattenberg, 1981a). Mice that have been fed BHA for 1 to 2 weeks in carcinogen inhibition experiments show marked in- creases in both glutathione S-transferase activity and tissue glutathione levels (Benson et al., 1978, 1979~. Glutathione S-transferase is an important enzyme for detoxifying chemical carcinogens (Benson et al., 1978; Jakoby, 1978; Wattenberg, 1981a). The activity of uridine diphos- phate (UDP)-glucuronyl transferase, which is another important conjugat- ing enzyme in the detoxification systems, is also increased (Cha and Bueding, 1979~. The feeding of BHA has also been reported to increase epoxide hydrolase activity (Cha et al., 1978) and to alter the microsomal monooxygenase system (Lam et al., 1980; Speier et al., 1978~. 15-3

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Inhibitors of Carcinogenesis 361 TABLE 15-1 Inhibition of Carcinogen-Induced Neoplasia by BHAa Carcinogen Inhibited Species Site of Neoplasm _ Benzo[a~pyrene Mouse Lung Benzo~a~pyrene Mouse Forestomach Benzo[a~pyrene-7-8-dihydrodiol Mouse 7,12-Dimethylbenz~aJanthracene Mouse Lung Forestomach, lung, and lymphoid tissue 7,12-Dimethylbenz~aJanthracene Mouse Forestomach 7,12-Dimethylbenz[aJanthracene Mouse Skin 7,12-Dimethylbenz~aJanthracene Rat Breast 7-Hydroxymethyl-12-methyl- Mouse Lung benz~aJanthracene Dibenz[_,h~anthracene Mouse Lung- Nitrosodiethylamine Mouse Lung 4-Nitroquinoline-N-oxide Mouse Lung Uracil mustard Mouse Lung Ure than Mouse Lung Methylazoxymethanol acetate Mouse Large intestine J trans-5-Amino-3-[2-(5-nitro-2- Mouse furyl~vinyl]-1,2,4-oxadiazole aFrom Wattenberg, 1979a. 15-4 Forestomach, lung, and lymphoid tissue

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362 DIET, NUTRITION, AND CANCER The amount of BHA consumed in the average U.S. diet is estimated to be several milligrams per day at most. This level, when corrected for body weight, is far less than that given to laboratory animals in experimental studies. However, exposure to carcinogens is almost cer- tainly orders of magnitude lower in the human population than in ex- perimental studies in animals. No conclusion can be drawn at this time as to whether inhibitory effects of BHA occur at the low concen- trations of carcinogens to which humans are generally exposed. Recent studies have shown that several naturally occurring phe- nolic compounds inhibit carcinogenesis in mice (Wattenberg et al., 1981a). The phenols studied thus far are cinnamic acid derivatives that are common constituents of plants. They include o-hydroxycinna- mic acid, p-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid (caffeic acid), and 4-hydroxy-3-methoxycinnamic acid (ferulic acid). Limited data on these derivatives indicate that their inhibition of benzo~a]- pyrene-induced neoplasia in the mouse is considerably weaker than that of BHA (Wattenberg et al., 1981a). There are many other phenols in plants, including plants consumed by humans, but their inhibitory activity is unknown. Indoles. Indole-3-acetonitrile, 3,3'-diindolylmethane, and indole-3-carbinol are found in edible cruciferous vegetables such as Brussels sprouts, cabbage, cauliflower, and broccoli. Indole-3- acetonitrile is the most abundant of the three. These indoles have been studied for their effects on neoplasia induced by benzo~aipyrene (BaP) and 7,12-dimethylbenz~aJanthracene (DMBA) in rodents (Wattenberg and Loub, 1978~. When added to the diet of mice before and during ad- ministration of BaP, all three indoles inhibited BaP-induced neoplasia of the forestomach and pulmonary adenoma formation. In other experi- ments, indole-3-carbinol and 3,3'-diindolylmethane inhibited DMBA- induced mammary tumor formation in female Sprague-Dawley rats. Indole- 3-acetonitrile was inactive in the rat (Wattenberg and Loub, 1978~. The original rationale for testing the three indoles stemmed from their ability to alter microsomal monooxygenase oxidase activity. All three compounds increased the activity of this enzyme system (Loub et al., 1975; Pantuck et al., 1976) -- indole-3-carbinol and 3,3'-di- indolylmethane more strongly than indole-3-acetonitrile. The three of them also increased glutathione S-transferase activity. There have been no studies in which these compounds were administered after the carcinogen. Aromatic Isothiocyanates. Benzyl isothiocyanates and phenethyl isothiocyanate are also constituents of cruciferous plants. These aromatic isothiocyanates have been shown to inhibit neoplasia induced by polycyclic aromatic hydrocarbons (PAH's) when they were adminis- tered during the initiation phase under several different experimental conditions. These results were obtained when the aromatic isothio- cyanate was fed both before and during administration of the PAM's 15-5

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Inhibitors of Carcinogenesis 363 (Wattenberg, 1977, 1979b). Little is known about their mechanism of inhibition other than the fact that benzyl isothiocyanate in a potent inducer of glutathione S-transferase activity. In further studies, mammary tumor formation resulting from exposure to DMBA was inhibited by the administration of benzyl isothiocyanate subsequent to the car- cinogen. It has also been demonstrated that this compound inhibited 1,2-dimethylhydrazine-induced neoplasia of the large intestine when the exposures were begun 1 week after administration of the carcinogen (Wattenberg, 1981b). The mechanism of these inhibitory effects is not known. Flavones. The study of flavones (found in fruits and vegetables) as possible inhibitors was undertaken as a result of data showing that several inducers of increased microsomal mixed function oxidase acti- vity inhibit chemically induced carcinogenesis. Inhibition of BaP-induced carcinogenesis has been studied with three flavones: two synthetic compounds -- 6-naphthoflavone (5,6- benzoflavone) and quercetin pentamethyl ether -- and one naturally occurring compound -- rutin (3,3',4',5,7-pentahydroxyflavone-3- rutinoside). Quercetin pentamethyl ether is sometimes substituted for tangeretin, a naturally occurring pentamethoxy flavone found in citrus fruits. All three flavones induce aryl hydrocarbon hydroxylase (AHH) activity: 6-naphthoflavone is the most potent inducer, quercetin pentamethyl ether is a moderate inducer, and rutin has the weakest inducing capacity. When added to the diet of A/HeJ mice subsequently challenged with orally administered BaP, 6-naphthoflavone caused almost total inhibition of pulmonary adenoma formation, and quercetin pentamethyl ether reduced the number of these neoplasms by one-half. The number of adenomas was the same in animals fed rutin and the con- trol diet. Thus, the inhibitory effects of BaP-induced neoplasia paralleled the potency of the three flavones in inducing increased AHH activity (Wattenberg and Leong, 1968, 1970~. Recently, 6-naphthofla- vone has been shown to induce activity of conjugating enzymes, includ- ing glutathione S-transferase. The mutagenic flavones have multiple hydroxyl groups. Flavones exerting protective effects do not have free polar groups; they either contain methoxy substituents or are unsubstituted (MacGregor and Jurd, 1978~. The mutagenic and carcinogenic effects of flavones are dis- cussed in Chapter 13. Protease Inhibitors. Protease inhibitors are widely distributed in plants, and are particularly abundant in seeds. Soybeans, a major source of protein in many vegetarian diets, and lima beans contain a variety of these compounds. Protease inhibitors have in common the ability to inhibit pro- tease enzymes as well as tumor promotion (Troll, 1981~. Inhibition of this type has been demonstrated using the two-stage model to study 15-6

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364 DIET, NUTRITION, AND CANCER skin carcinogenesis in the mouse. In addition, a reduced incidence of breast cancer has been observed in irradiated rats fed a diet rich in protease inhibitors after exposure to the radiation (Troll, 1981~. Protease inhibitors have also been shown to block promotion in in vitro systems. The transformation of C3HlOTl/2 cells by x-rays fol- lowed by incubation with 12-o-tetradecanoylphorbol-13-acetate (TPA) is blocked if protease inhibitors are present after exposure to the radi- ation (Kennedy and Little, 1981~. Troll (1980) suggested that pro- tease inhibitors prevent formation of free radicals by tumor promoters. Since BRA and some related antioxidants inhibit promotion, there may be common mechanisms among inhibitors that would lead to synergistic effects. 6-Sitosterol. 6-Sitosterol is a common plant sterol that is pres- ent in many different vegetables and vegetable oils. Its protective effects have been studied in an experimental system with N-nitroso- methylurea--a direct-acting carcinogen. 6-Sitosterol reduced the in- cidence of large bowel cancer from 54% to 33% when fed in the diet through the entire course of the experiment or only during the promo- tion phase of carcinogenesis (Cohen and Raicht, 1981; Raicht et al., 1980~. Other plant sterols of similar structure have not been studied for potential inhibitory effects. Effects of Individual Foods on Carcinogen-Metabolizing Enzyme Systems Studies in Animals. Several enzyme systems involved in metaboliz- ing carcinogens are highly responsive to compounds entering the body from the environment. For example, animals fed purified diets and kept in filtered air show almost no monooxygenase oxidase activity for PAM's and azo dyes in the small bowel and lungs (Wattenberg, 1970, 1972). One source of naturally occurring inducers of increased microsomal monooxygenase activity is vegetables. In laboratory animals, crucif- erous vegetables such as Brussels sprouts, cabbage, cauliflower, and broccoli have a moderately potent inducing effect on monooxygenase oxidase activity. Other vegetables such as alfalfa, spinach, and celery have some inducing activity, but it is weak (Wattenberg, 1972~. More recently, studies have been conducted to examine the effects of individual foods on glutathione S-transferase, which is a major detoxification system that catalyzes the binding of a vast variety of electrophiles to the sulfhydryl group of glutathione (Chasseaud, 1979; Jakoby, 1978~. Since the reactive ultimate carcinogenic forms of chem- icals are electrophiles, the glutathione S-transferase system takes on considerable importance as a mechanism for carcinogen detoxification. Enhancement of the activity of this system, as measured in vitro, has been shown to be associated with decreased response of tissues to chemical carcinogens (Sparnins and Wattenberg, 1981~. 15-7

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Inhibitors of Carcinogenesis 365 The activity of glutathione S-transferase is much greater in tis- sues of animals fed normal rather than purified diets. Diets contain- ing large quantities of cruciferous vegetables induce increased gluta- thione S-transferase activity (Sparnins, 1980~. The extent to which green coffee beans induce such activity is quite remarkable. In mice fed a diet containing green coffee beans, glutathione S-transferase activity was enhanced sixfold in the liver and sevenfold in the small bowel (Sparnins et al., 1981~. Considerably less inducing activity has been found in roasted coffee beans, commercial instant coffee, and instant decaffeinated coffee, indicating that some destruction of the inducing compounds has occurred during processing. Two potent inducers of glutathione S-transferase activity have been isolated from green coffee beans. These compounds are kahweol palmitate and cafestol palmitate (Lam et al., 1982~. Studies in Humans. Diets containing large amounts of cabbage and Brussels sprouts were fed to healthy volunteers between 21 and 32 years of age. The effects of this diet on the metabolism of antipyrine and phenacetin were studied. These compounds, like many carcinogens, are initially metabolized by the microsomal monooxygenase system and their oxidative metabolites subsequently conjugated. The results indicated that subjects eating diets rich in vegetables metabolized both drugs more rapidly than did subjects on a control diet (Pantuck et al., 1979). Possible Adverse Effects of Inhibitors Several of the inhibitors discussed above, e.g., indole-3-carbinol and 3,3'-diindolylmethane, are moderate or strong inducers of micro- somal monooxygenase activity. Compounds with this characteristic are potentially hazardous (Wattenberg, 1979a). For example, the micro- somal monooxygenase enzyme system produces two different categories of carcinogen metabolites: detoxification products and activated species. In the metabolism of aromatic amines, ring hydroxylation results in de- toxification, whereas hydroxylation of the nitrogen leads to the forma- tion of a proximate carcinogen. Thus, administration of compounds that increase monooxygenase activity can result in competing reactions, and the net effect is uncertain. A second possible adverse effect of compounds that induce micro- somal monooxygenase activity is that they may act as tumor promoters. An additional consideration is that the microsomal monooxygenase sys- tem metabolizes some physiological compounds such as steroid hormones. This alteration of activity might cause adverse effects by changing the levels of these compounds or their metabolites. Two compounds have been shown experimentally to have dual effects, i.e., they can inhibit carcinogenesis and they also can cause or en- hance neoplasia. One such compound is butylated hydroxytoluene (BHT). This compound can inhibit carcinogenesis under certain conditions. It is also a tumor promoter, as discussed in Chapter 14. The second com- pound is coumarin, which can inhibit carcinogenesis, but when fed to 15-8

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366 DIET, NUTRITION, AND CANCER rats for 18 months, it produces bile duct carcinomas. Thus, a particu- lar compound may have diverse effects. When this occurs, its overall impact is difficult to predict. S UMMARY Epidemiological Studies Epidemiological evidence from several case-control studies suggests that certain vegetables, especially cruciferous vegetables, have a possible protective effect against cancer at several sites. The responsible constituent or constituents cannot be identified on the basis of present information. Experimental Studies Food contains many compounds that have been shown to inhibit carcinogenesis in laboratory animals. Because there are so many of these compounds and because their nature is so diverse, they are likely to be present in the diet of most humans. The mechanisms of inhibition are incompletely understood. Some inhibitors modify the activity of enzyme systems that have the capa- city to detoxify carcinogenic agents. Others may act by suppressing formation of free radicals or by trapping free radicals arising during the process of carcinogenesis. A number of compounds inhibiting chemically induced carcinogenesis in laboratory animals are present in cruciferous vegetables. These compounds include aromatic isothiocyanates, indoles, and phenols. CONCLUSION The committee concluded that there is sufficient epidemiological evidence to suggest that consumption of certain vegetables, especially carotene-rich (i.e., dark green and deep yellow) vegetables and cru- ciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels sprouts), is associated with a reduction in the incidence of cancer at several sites in humans. A number of nonnutritive and nutritive com- pounds that are present in these vegetables also inhibit carcinogenesis in laboratory animals. Investigators have not yet established which, if any, of these compounds may be responsible for the protective effect observed in epidemiological studies. The fact that a compound has been shown to inhibit carcinogen- induced neoplasia in laboratory animals should not be interpreted as indicating that it is desirable for humans. These compounds may have adverse effects. Information on this subject is incomplete. 15-9

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Inhibitors of Carcinogenesis 367 REFERENCES Batzinger, R. P., S.-Y. L. Ou, and E. Bueding. 1978. Antimutagenic effects of 2~3~-tert-butyl-4-hydroxyanisole and of antimicrobial agents. Cancer Res. 38:4478-4485. Benson, A. M., R. P. Batzinger, S.-Y. L. Ou, E. Bueding, Y.-N. Cha, and P. Talalay. 1978. Elevation of hepatic glutathione S- transferase activities and protection against mutagenic metab- olites of benzota~pyrene by dietary antioxidants. Cancer Res. 38 :4486-4495. Benson, S. M., Y.-N. Cha, E. Bueding, H. S. Heine, and P. Talalay. 1979. Elevation of extrahepatic glutathione S-transferase and epoxide hydratase activities by 2~3~-tert-butyl-4-hydroxyanisole. Cancer Res. 39:2971-2977. Bjelke, E. 1978. Dietary factors and the epidemiology of cancer of the stomach and large bowel. Aktuel. Ernaehrungsmed. Klin. Prax. Suppl. 2:10-17. Cha, Y.-N., and E. Bueding. 1979. Effect of 2~39-tert-butyl-4- hydroxyanisole administration on the activities of several hepatic microsomal and cytoplasmic enzymes in mice. Biochem. Pharmacol. 28: 1917-1921. Cha, Y.-N., F. Martz, and F. Bueding. 1978. Enhancement of liver microsome epoxide hydratase activity in rodents by treatment with 2~3~-tert-butyl-4-hydroxyanisole. Cancer Res. 38:4496-4498. - Chasseaud, L. F. 1979. The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv. Cancer Res. 29:175-274. Cohen, B. I., and R. F. Raicht. 1981. Plant sterols: Protective role in chemical carcinogenesis. Pp. 189-201 in M. S. Zedeck and M. Lipkin, eds. Inhibition of Tumor Induction and Development. Plenum Press, New York and London. Graham, S., W. Schotz, and P. Martino. 1972. Alimentary factors in the epidemiology of gastric cancer. Cancer 30: 927-938. Graham, S., H. Dayal, M. Swanson, A. Mittelman, and G. Wilkinson. 197 8. Diet in the epidemiology of cancer of the colon and rectum. J. Natl. Cancer Inst. 51: 709-714. 15-10

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368 DIET, NUTRITION, AND CANCER Haenszel, W., M. Kurihara, M. Segi, and R. K. C. Lee. 1972. Stomach cancer among Japanese in Hawaii. J. Natl. Cancer Inst. 49:969-988. Haenszel, W., J. W. Berg, M. Segi, M. Kurihara, and F. B. Locke. 1973. Large-bowel cancer in Hawaiian Japanese. J. Natl. Cancer Inst. 51:1765-1779. Haenszel, W., M. Kurihara, F. B. Locke, K. Shimuzu, and M. Segi. 1976. Stomach cancer in Japan. J. Natl. Cancer Inst. 56:265-274. Haenszel, W., F. B. Locke, and M. Segi. 1980. A case-control study of large bowel cancer in Japan. J. Natl. Cancer Inst. 64:17-22. Hirayama, T. 1977. Changing patterns of cancer in Japan with special reference to the decrease in stomach cancer mortality. Pp. 55-75 in H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds. Origins of Human Cancer, Book A: Incidence of Cancer in Humans. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. Jakoby, W. B. 1978. The glutathione _-transferases: A group of multifunctional detoxification proteins. Adv. Enzymol. Relat. Areas Mol. Biol. 46:383-414. Kennedy, A. R., and J. B. Little. 1981. Effects of protease inhibitors on radiation transformation in vitro. Cancer Res. 41:2103-2108. Lam, L. K. T., A. V. Fladmoe, J. B. Hochalter, and L. W. Wattenberg. 1980. Short time interval effects of butylated hydroxyanisole on the metabolism of benzo~a~pyrene. Cancer Res. 40:2824-2828. Lam, L. K. T., V. L. Sparnins, and L. Wattenberg. 1982. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse. Cancer Res. 42:1193-1198. Loub, W. D., L. W. Wattenberg, and D. W. Davis. 1975. Aryl hydro- carbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. J. Natl. Cancer Inst. 54:985-988. MacGregor, J. T., and L. Jurd. 1978. Mutagenicity of plant flavo- noids: Structural requirements for mutagenic activity in Salmo- nella typhimurium. Mutat. Res. 54:297-309. MacLennan, R., J. Da Costa, N. E. Day, C. H. Law, Y. K. Ng, and K. Shanmugaratnam. 1977. Risk factors for lung cancer in Singapore Chinese, a population with high female incidence rates. Int. J. Cancer 20:854-860. 15-11

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Inhibitors of Carcinogenesis 369 Modan, B., V. Barrell, F. Lubin, M. Modan, R. A. Greenberg, and S. Graham. 1975. Low-fiber intake as an etiologic factor in cancer of the colon. J. Natl. Cancer Inst. 55:15-18. Pantuck, E. J., K.-C. Hsiao, W. D. Loub, L. W. Wattenberg, R. Kuntzman, and A. H. Conney. 1976. Stimulatory effect of vegetables on intestinal drug metabolism in the rat. J. Pharmacol. Exp. Ther. 198:278-283. Pantuck, E. J., C. B. Pantuck, W. A. Garland, B. H. Min. L. W. Wattenberg, K. E. Anderson, A. Kappas, and A. H. Conney. 1979. Stimulatory effect of Brussels sprouts and cabbage on human drug metabolism. Clin. Pharmacol. Ther. 25:88-95. Raicht, R. F., B. I. Cohen, E. P. Fazzini, A. N. Sarwal, and M. Takahashi. 1980. Protective effect of plant sterols against chemically induced colon tumors in rats. Cancer Res. 40:403-405. Slaga, T. 1981. Food additives and contaminants as modifying factors in cancer induction. Prog. Cancer Res. Ther. 17:279-290. Sparnins, V. L. 1980. Effects of dietary constituents on gluta- thione-S-transferase (G-S-T) activity. Proc. Am. Assoc. Cancer Res. Am. Soc. Clin. Oncol. 21:80. Abstract 319. Sparnins, V. L., and L. W. Wattenberg. 1981. Enhancement of gluta- thione S-transferase activity of the mouse forestomach by inhibitors of benzo~aipyrene-induced neoplasia of forestomach. T Natl. Cancer Inst. 66:769-771. Sparnins, V. L., L. K. T. Lam, and L. W. Wattenberg. 1981. Effects of coffee on glutathione S-transferase (G S T) activity and 7,12-dimethylbenz~ajanthracene (DMBA)-induced neoplasia. Proc. Am. Assoc. Cancer Res. Am. Soc. Clin. Oncol. 22:114. Abstract 453. Speier, J. L., L. K. T. Lam, and L. W. Wattenberg. 1978. Effects of administration to mice of butylated hydroxyanisole by oral intubation on benzo~a~pyrene-induced pulmonary adenoma formation and metabol~sm of benzo~a~pyrene. J. Natl. Cancer Inst. 60:605-609. Troll, W. 1981. Blocking of tumor promotion by protease inhibitors. Pp. 549-555 in J. H. Burchenal and H. F. Oettgen, eds. Cancer: Achievements, Challenges and Prospects for the 1980's, Volume 1. Grune and Stratton, New York, London, Toronto, Sydney, and San Francisco. Wattenberg, L. W. 1970. The role of the portal of entry in inhibi- tion of tumorigenesis. Prog. Exp. Tumor Res. 14:89-104. 15-12

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370 DIET, NUTRITION, AND CANCER Wattenberg, L. W. 1972. Enzymatic reactions and carcinogenesis. Pp. 241-254 in Environment and Cancer. Williams and Wilkins Company, Baltimore, Md. Wattenberg, L. W. 1977. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J. Natl. Cancer Inst. 58:395-398. Wattenberg, L. W. 1978. Inhibitors of chemical carcinogenesis. A`lv. Cancer Res. 26:197-226. Wattenberg, L. W. 1979a. Inhibitors of chemical carcinogens. Pp. 241-263 in P. Emmelot and E. Kriek, eds. Environmental Carcino- genesis. Elsevier/North-Holland Biomedical Press, Amsterdam. Wattenberg, L. W. 1979b. Naturally occurring inhibitors of chemical carcinogenesis. Pp. 315-329 in E. C. Miller, J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md. Wattenberg, L. W. 1981a. Inhibitors of chemical carcinogens. Pp. 517- 539 in J. H. Burchenal and H. F. Oettgen, eds. Cancer: Achieve- ments, Challenges, and Prospects for the 1980's, Volume 1. Grune and Stratton, New York, London, Toronto, Sydney, and San Francisco. Wattenberg, L. W. 1981b. Inhibition of carcinogen-induced neoplasia by sodium cyanate, tert-butyl isocyanate and benzyl isothiocyanate administered subsequent to carcinogen exposure. Cancer Res. 41:2991-2994. Wattenberg, L. W., and J. L. Leong. 1968. Inhibition of the carcino- genic action of 7 , 12-dimethylbenz~a janthracene by beta-naphthofla- vone. Proc. Soc. Exp. Biol. Med. 128: 940-943. Wattenberg, L. W., and J. L. Leong. 1970. Inhibition of the carcino- genic action of benzota~pyrene by flavones. Cancer Res. 30:1922- 1925. Wattenberg, L. W., and W. D. Loub. 1978. Inhibition of polycyclic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res. 38:1410-1413. Wattenberg, L. W., J. B. Coccia, and L. K. T. Lam. 1980. Inhibitory effects of phenolic compounds on benzo~a~pyrene-induced neoplasia. Cancer Res. 40:2820-2823. 15-13

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Section C Patters of Diet and Cancer In Sections A and B the committee reviewed the evidence concerning the role of specific nutrients and nonnutritive dietary components. This section provides a more comprehensive assessment of the overall contribution of diet to cancer. Chapter 16 contains an overview of the evidence relating diet to cancer in light of the trends in cancer incidence and mortality and the influence of other environmental factors on these trends. In Chapter 17, the epidemiological evidence is reassembled by each cancer site to provide a perspective on the contribution of all dietary factors to the occurrence of cancer at specific sites. The committee recognized at the start that the current state of knowledge is insufficient to permit a precise quantification of the effect of the diet on the incidence of cancer. Therefore, in Chapter 18, the committee has presented merely a framework for assessing risk, with particular emphasis on the different elements that need to be con- sidered when assessing the risks posed by initiators and modifiers that may be present in the diet. Attempts made by other investigators to determine the quantitative contribution of diet to the overall risk of cancer are also discussed. 371 C-1