Strong epidemiologicel evidence implicates diet in a substantial proportion of cancer cases. Nutritionists largely agree on the attributes of a healthy diet for cancer prevention (and also for cardiovascular health). Researchers are now studying specific food components that can actively suppress the processes involved in carcinogenesis, The most potent of these could be used directly for chemoprevention in high-risk individuals and might even have potential in cancer therapy,

EPIDEMIOLOGICAL, animal, laboratory and human case-control and cohort studies have shown that different foods can incrcasc or de- crease cancer risk at many sites in the body (Boxes I, 2) ~.:. Nutritional epidemiologists now agree that a diet low in fat, alcohol and salty foods but high in fruit, vegetables and plant-derived protein is likely to decrease the risk of developing cancer and cardiovascular disease.

Foods that increase cancer risk Despite the commonly accepted hypothesis that a third of all cancers are caused by components in the diet, few can be linked specifically to individual dietary components (see Box 1). Alcohol, preserved foods and 'mouldy' foods probably account for only -5% of all cancer cases. The other +25% of cancers that are thought to be preventable by dietary modification have been associated with meat and fat intake (see Box 1), but the evidence for cause and effect is more contentious. Com- plications arise when observational studies in human populations at- tempt to back up findings from laboratory and epidemiological studies. For example, human experimental studies have confirmed the results of epidemiological studies in showing that a diet high in animal-derived fat is a significant risk factor for prostate cancer 3,4. However, most case- control and cohort studies of breast cancer have failed to confirm a link between intake of fat in adulthood or childhood and subsequent cancer risk s. In a recent review, Jennifer Kelsey (Professor of Health Research and Policy, Stanford University School of Medicine, Palo Alto, CA, USA) highlights the difficulties inherent in designing epidemiological studies to test dietary hypotheses. 'The extent of measurement error makes observation studies likely to be inconclusive. Since any effect of diet is probably small at most, randomized trials would have to be of such size that they would be almost prohibitively expensive. Not only are the roles of specific dietary constituents unclear, but the age at which they are likely to have an effect is unknown.'

Foods that decrease cancer risk Foods that are linked with cancer development can be avoided to reduce cancer risk, but it also seems likely that eating certain foods can have a positively protective effect,

Fibre and cancer prevention Studies of colorectal cancer have demonstrated one of the most posi- tive associations between cancer risk and the lack of a dietary com-

Copyright ©1997 Elsevier Science Ltd. All rights reserved. 1357 - 4310/97/$17.00 Pn: Sl357-4310(97)01002-2

ponent. A meta-analysis of 13 case-control studies from 9 countries concluded that fibre intake is inversely related to cancers of both the colon and the rectum 6. The term fibre is used to describe a complex mixture of compounds including insoluble fibre (e.g. wheat bran and cellulose) and soluble fibre (e.g. dried beans). Ingestion of fibre could modify carcinogenesis in the large bowel by a number of potential mechanisms - by binding to bile acids, by increasing stool weight, by decreasing transit time in the gut and by acting as a sub- strate for bacterial fermentation. Increased bacterial fermentation leads to an increase in bacterial mass and production of short-chain fatty acids such as butyrate. Butyrate has been shown to have anti- carcinogenic effects in vitro 7.

Although the weight of evidence strongly suggests that fibre pro- tects against colorectal cancer, some researchers are still cautious. Wasan and Goodlad have underlined the difficulty in interpreting epi- demiological and analytical studies on diet and have posed the ques- tion, 'Is a diet high in fibre associated with a reduced risk of colo- rectal cancer because of its fibre content per se, or some other constituent of the fibre-rich foods being consumed?'S.

Fruits' and vegetables and cancer protection Over 200 studies have examined the relationship between fruit and vegetable intake and cancer at selected sites. The majority have con- cluded that consumption of these foods offers a significant protec- tive effect against cancer 9. Eating fruit and/or vegetables has been shown to be protective against: lung cancer (24 of 25 studies, in most instances after control for smoking); tumours of the oesopha- gus, oral cavity and larynx (28 of 29 studies); pancreas and stomach cancers (26 of 30 studies); colorectal and bladder cancers (23 of 38 studies); malignancies of the cervix, ovary and endometrium (11 of 13 studies); and breast cancer, where a protective effect was found to be strong and consistent in meta-analysis. Overall, the relative risk of cancer was about twice as high for those eating few fruits and vegetables compared with those who ate plenty of these foods.

Timothy Key of the Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, UK, who recently published the latest results of a study of vegetarians and bealth-conscious people 1°, comments, 'It is difficult for a single study to produce a definitive result but all of the studies carried out during the last 30 years strongly suggest that eat- ing fresh fruit and fresh vegetables is probably the most important

1 0 3

| ~ , ~ ~ i,~ ! i , M O L E C U L A R M E D I C I N E T O D A Y , M A R C H 1 9 9 7

Strong evidence Alcohol - Drinking lmge aln.~tnt: strongly inked to 2~4(4 of all canq dose-dependent association hetwe the oesophagus, mouth, pha~,nx i increases the risk of liver, breast,i sistent. For liver cancer, for cxamii viral infection are almost impossii of alcohol t~', Ethanol itself is not ~i cinogenic effects of other chemi oesophageal cancer is, for exampi drink than in people who either i alcohol could initiate and promo i oncogenes j'~. Acetaldehyde, produi cellular DNA repah', allowing pot~ i mulate at a faster rate than normal J

Traditional preservative~ - Th methods of preserving food - s cancer of the oesophagus, stoma, in the USA and Europe, but hig fish and pickled vegetables are not an option. The effect of eatin obvious in veo, young children, of the nasopharynx :°. A recent showed that salt intake correlate that a high salt intake exacerbat sumed in food2L

Aflatoxins - Contaminated foods toxins produced by fungi of the A,, are strongly suspected of causing major afiatoxins, two, B1 and Gt of cancer in different animal spec, i:i ered by the hltemational Agency cinogen. Human liver tumours tii characteristic mutational profile i~ ber of epidemiological studies c~ i that the incidence of liver canceli aflatoxins ingested in the diet, Ho i of viral heoatitis, are clearlv invol~

More controversial dietary risk Meat - Eating a diet high in me risk of developing stomach and c

dietary change that anyone can make if they are aiming to reduce their risk of developing the chronic diseases of middle-age.'

The search for c o m p o u n d s t h a t p r o t e c t a g a i n s t c a n c e r While lifestyle changes are being actively promoted in the USA, Australia and Europe, research is also continuing to discover which components of specific foods interfere with the process of carcinogen-

esis in vitro and protect against cancer in animal models and in human studies. Several likely compounds have already been isolated and testing is under way (Table 1).

Anti-oxidant vitamins A large number of observational analytical studies, using both case- control and prospective cohort designs, have shown inverse associations

1 0 4

M O L E C U L A R MEDICINE TODAY, M A R C H 1997 P ~ ) r,~¢"~ [ ) e C ~ ~ ~ '~%

between either dietary intake or blood levels of antioxidant vitamins and risks of cancer. Several trials have been carried out to further test the hypothesis that vitamins might protect against cancer - four of these have reported during the past three years.

The Chinese Cancer Prevention Trial 11 looked at the preventive effects of several vitamins and minerals in a population with one of the world's highest rates of oesophageal and gastric cancer. Concluded in 1993, it showed that people given a combination of [3-carotene, vitamin E and selenium had a 9% lower mortality and a significant (21%) decrease in deaths from gastric cancer compared with those who had received no supplements. A year later, researchers sponsored by the US National Cancer Institute (NCI) published the results of the a-tocopherol, 13-carotene Cancer Prevention Study (ATBC) 12, reporting that Finnish men who took 13-carotene supplements had 18% more lung cancers and an 8% increase in overall mortality.

In January 1996, Charles Hennekens and his colleagues at Harvard University (MA, USA) announced that the Physicians' Health study had showed that taking supplements had no effect on cancer incidence in non-smoking participants 13. More alarmingly, interim results of the [3-carotene and Retinol Efficacy Trial (CARET) showed a 28% increase in the incidence of lung cancer and a 17% increase in overall mortality rates in long-term smokers and people exposed to asbestos*. On the balance of evidence that vitamins might be increasing cancer risk in subjects who were already at high risk, researchers decided to interrupt the CARET study, and told the participants to stop taking their supplements.

*Reported in a National Cancer Institute bulletin, available on the World Wide Web at: http://cancernet'nci'nih'g°v/clinpdq/bulletins/Cigarettes °r-Alc°h°l-May Enhance- Adverse_Effects_of_B eta Carotene.html

These results have puzzled researchers. In 1993, Demetrius Albanes, leader of the group that carried out the ATBC trial, com- mented, 'The results [of the ABTC trial] are contrary to data from epi- demiological studies suggesting that B-carotene in the diet is associ- ated with a lower risk of lung cancer. The lack of benefit for [3-carotene in our study, coupled with the possibility of harm, was very unexpected.' Peter Greenwald, director of NCI's Division of Cancer Prevention and Control, comments: 'The results are disappointing, but they illustrate the value of clinical trials. Before, it wasn't possible to separate what might be a specific effect of [3-carotene from the overall effect of fruits or vegetables. Now that we know [3-carotene isn't the cancer-preventer in foods, it raises the question of the need to take sup- plements at all. We would still recommend that people eat plenty of fruit and vegetables rather than relying on supplements. In the future, we will concentrate on other components of fruits and vegetables that are responsible for their ability to protect against cancer.'

Protective phytochemicals Other scientists have reached the same conclusion, and detailed mol- ecular studies are just starting to provide new information about the role of phytochemicals in preventing and potentially treating cancers (Table 1).

To learn which compounds in edible plants are most likely to be active, Paul Talalay (Head of the Brassica Chemoprotection Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA) and colleagues have developed a cell culture system using murine hepatoma cells for identifying chemoprotcctive chemicals present in edible vegetables. The research still has a long way to go but a few phytochemicals are showing great promise. Sulphoraphane, an isothiocyanate found in cruciferous vegetables such as watercress and broccoli, has been found to reduce the

105

Perspecti y e s M O L E C U L A R M E D I C I N E T O D A Y , M A R C H 1 9 9 7

Table 1.

Chemical

Anti-oxidant vitamins t3-carotene

Vitamin C

Vitamin E

Phytoehemicals Sulphoraphane

Mono-terpenes such as limonene, perillyl alcohol

Polyacetylenes

Sulphur compounds

Phenolic compounds

Ellagic acid

Flavonoids, such as genistein, daidzein, quercetin, silymarin

Data taken from Refs 26, 27, ',

incidence, number, size and rate of development of experimentally induced mammary tumours in rats. Isothiocyanates seem to work as anti-cancer agents by inhibiting the phase 1 enzymes that metaboli- cally activate carcinogens. Many are also inducers of phase 2 enzymes, which inhibit carcinogenesis by detoxification. The balance between phase 1 and phase 2 enzymes seems to be a major determi- nant of the outcome following exposure to carcinogens.

Narrowing down the phytochemicals involved in cancer protection is easier when evidence points to individual foods, rather than groups of foods. There is some epidemiological evidence that soy products and green tea can protect against specific cancers, and researchers looking into the disease-prevention qualities of these plant foods are focusing on phytoestrogens (plant compounds that mimic oestrogens).

1 0 6

Of the phytoestrogens, flavonoids and isoflavonoids are of particu- lar interest. A group at the University of Alabama Department of Pharmacology and Toxicology (AL, USA) are looking at the effects of genistein, an isoflavonoid. They recently published the results of a study on newborn female rats that were exposed to a carcinogen known to induce mammary tumours later in life and then given genis- tein or a control compound 14. All of the rats receiving the control com- pound developed tumours, whereas only 60% of the rats receiving genistein got cancer. Coral Lamartiniere, leader of the group, said 'This study is the first to show in vivo that genistein can protect against chemically induced cancer. Genistein might exert its action at a number of points along the "carcinogenesis pathway", modifying cell proliferation through inhibition of key proteins, targeting metabolic pathways that control mutagenesis and inhibiting cell proliferation

M O L E C U L A R M E D I C I N E T O D A Y , M A R C H 1 9 9 7 Perspectives

and angiogenesis, the process by which tumours grow new blood vessels.'

It is clear that many of the most promising protective phytochemi- cals cannot be ingested in sufficient quantity to have any sort of thera- peutic effect, if their only source is ordinary vegetables. Researchers working on limonene, a particularly potent anti-cancer chemical found in orange peel, estimate that a patient would need to eat 400 oranges a day to obtain a therapeutic level of the compound. Future research could go in several directions to solve this problem: (1) the protective compound could be purified, concentrated and used directly as a food supplement or a drug for prevention or therapy; (2) analogues could be designed and developed in a similar way to any plant-based pharmaceutical; and (3) genetic engineering could pro- duce plants that are excessively rich in the compound. Whatever the method of delivering therapeutic doses, it seems likely that we will see the start of large-scale trials of anti-cancer phytochemicals in the relatively near future. If these produce promising results, chemopre- vention trials among high-risk groups will follow.

References 1 Doll, R. and Peto, R. (1982) The causes of cancer, Oxford University Press 2 Willet, W.C. (1994) Diet and health: what should we cat? Science 264, 532-537 3 Pienta, K.J. and Esper, P.S. (1993) Risk factors for prostate cancer, Ann. Intern.

Med. 118, 793-803 4 Whittemore, A.S. et al. (1995) Prostate cancer in relation to diet, physical activ-

ity and body size in blacks, whites and Asians in the USA and Canada, J. Natl.

Cancer Inst. 87, 652-660 5 Kelsey, J.L and Gammon, M.D. (1991) The epidemiology of breast cancer,

Cancer J. Clinicians 41, 146-165 6 Howe, G.R. et al. (1992) Dietary intake of fibre and decreased risk of cancers of

the colon and rectum: evidence from the combined analysis of 13 case-control studies, J. Natl. Cancer Inst. 84, 1887-1896

7 Jacobs, L.R. (1986) Relationship between dietary fibre and cancer: metabolic, physiologic and cellular mechanisms, Proc. Soc. Exp. Biol. Meal. 183, 29%310

8 Wasan, H.S. and Goodlad, R.A. (1996) Fibre-supplemented foods may damage your health, Lancet 348, 219-220

9 Block, G., Patterson, B. and Subar, A. (1992) Fruit, vegetables and cancer pre-

vention: a review of the epidemiological evidence, Nut~ Cancer 18, 1-29 10 Key, T.J.A., Thorogood, M., Appleby, P.N. and Burr, M.L. (1996) Dietary habits

and mortality in 11000 vegetarians and health conscious people: results of a 17 year follow-up, Br. Med. J. 313, 775-778

11 Blot, W.J. et al. (1993) Nutrition intervention trials in Linzian, China: sup- plementation with specific vitamin/mineral combinations, cancer incidence, and dis- e a s e - ~ mortality in the general population, J. Natl. Cancerlnst. 85,1483-1492

12 The a-tocopherol, 13-carotene Cancer Prevention Study Group (1994) The effect of vitamin E and I~-carotene on the incidence of lung cancer and other cancers in male smokers, New Engl. J. Med. 330, 102%1035

13 Buring, J.E. and Hennekens, C.H. (1995) Antioxidant vitamins and cancer: the physicians' health study and women's health study, in Nutrients in Cancer Pre-

vention and Treatment (Prasad, K.N., Santamaria, L. and Williams, R.M., eds), pp. 223-234, Humana Press

14 Ziegler, J. (1994) Soybeans show promise in cancer prevention, J. Natl. Cancer

Inst. 86, 1666 15 Rothraan, K.J. (1980) The proportion of cancer attributable to alcohol con-

sumption, Prey. Med. 9, 174-179 16 National Institute on Alcohol Abuse and Alcoholism (1993) Alcohol and cancer,

Alcohol Alert 21,345 17 Garro, A.J. and Licbcr, C.S. (1990) Alcohol and cancer, Annu. Re~: Pharm.

Toxicol. 30, 219-249 18 Kharbanda, S., Nakamura, T. and Kufe, D. (1993) Induction of the c-jun proto-

oncogene by a protein kinase C-dependent mechanism during exposure of human epidermal keratinocytes to ethanol, Biochem. Pharmacol. 45, 675-681

19 Espina, N., Lima, V., Lieber, C.S. and Garro, A.J. (1988) In vitro and in vivo

inhibitory effect of ethanol and acetaldehyde on 0-6 methylguanine transferase, Carcinogenesis 9, 761-766

20 Anon. (1989) F_,ditorial: S a k t e d f i s h a n d n a s ~ c a r d n o m a , Lancet334, 840-842

21 Joossens, J.V. et al. (1996) Dietary salt, nitrate and stomach cancer mortality in 24 countries, Int. J. Epidemiol. 25, 494-504

22 Kleman, M.I. and Overvik, E. (1995) Carcinogens formed during cooking, in Mechanistic Approaches to Cancer (Drugs, Diet and Disease Vol. 1) (Ioannides, C. and Lewis, D.EV., eds), pp. 65-93, Ellis Hurwood

23 Robbana-Barnat, S., Rabache, M., Rialland, E. and Fradin, J. (1996) Heterocyclic amines: occurrence and prevention in cooked food, Environ. Health Perspect.

104, 280-288 24 Reddy, B.S. et al. (1976) Effect of quality and quantity of dietary fat and

dimethylhydrazine in colon carcinogenesis in rats, Proc. Soe. Exp. Biol. Med.

151,237-239 25 Nanss, K.M., Locniskar, M. and Newbeme, P.M. (1983) Effect of alterations in

the quality and quantity of dietary fat on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats, Cancer Res. 43, 4083-4090

26 Miller, A.B. (1977) Role of nutrition in the etiology of breast cancer, Cancer 39 (Suppl. 6), 2704-2708

27 Bluell, P. (1973) Changing incidence of breast cancer in Japanese American women, J. Natl. Cancer Inst. 51, 147%1483

28 Rose, D.P., Connolly, J.M., Raybum, J. and Coleman, M. (1995) Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice, J. Natl. Cancer Inst. 87, 587-592

29 Zhang, Y., Talalay, P., Cho, G-C. and Posner, G.H. (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure, Proc. Natl. Acad. Sci. U. S. A. 89, 2399-2403

30 Marwick, C. (1995) Learning how phytochemicais help fight disease, J. Am.

Meal. Assoc. 274, 1328-1330 31 Wiesberger, J.H. (1991) Nutritional approach to cancer prevention with emphasis

on vitamins, antioxidants and carotenoids, Am. J. Clin. Nutr. 53 (Suppl.), 226S-237S

iathr n Senior is a freelance science write

l

1 0 7