**3. Diet and carcinogenesis**

number of descriptive, ecological and epidemiological studies. Studies by Doll and Peto indicated the importance of antioxidants, leafy vegetables, fish and several other bioactive micronutrients in cancer prevention [7].In 1982, The National Academy of Sciences in USA proposed six interim guidelines to reduce the risk of cancer [8]. This included reduction of dietary fat, increased consumption of food rich in fruits and vegetables, salt restriction, decreased intake of smoked food-stuffs and reduced intake of alcohol. This review will discuss

As mentioned in the introduction, cancer is a major cause of mortality throughout the world. In developed and fast-growing countries, the mortality due to cancer is generally exceeded only by mortality from cardiovascular diseases. According to a report in the Lancet in 1977, the World Health Organization (WHO) identified the 4 of the 10 leading causes of mortality worldwide. They are from Ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease and lung cancer. In an earlier report, the fourth leading cause of death worldwide was due to nutritional disorders. The authors in that report predicted that even in 2020, the fourth leading cause of death would be due to nutritional disorders [11]. The incidence of lung cancer is likely to increase in the coming decades, especially in fast-growing countries like China, India, Brazil, South Africa and Russia (BRICS) due to smoking, environ‐ mental pollution and other unknown factors. The incidence of cancer in our ancestors (gatherhunters and pastoral people) living in remote areas of the globe was very low. The average lifespan on the other hand was very low in those days. According to some experts, the dramatic shift away from the eating habits of our ancestors is probably responsible for fostering many of the "diseases of civilization" including cancer [12]. For males and females taken together,

some important concepts in cancer prevention by diet modification.

180 Pharmacology and Nutritional Intervention in the Treatment of Disease

the incidence of most of the common cancers are shown in Table 1.

**Table 1.** Estimated number of new cases in men and women in 1996

**Cancer site Males(%) Females (%)** Lung 18.6 6.7 Stomach 11.9 7.6 Colorectal 8.4 8.6 Prostate 7.5 — Breast — 18.6 Oro-Pharyngeal 7.3 3.8 Esophagus 6.1 — Bladder 4.4 — Liver 7.1 — Ovary — 3.9 Others 28.8 17.4

**2. Cancer pattern**

Like many other chronic diseases, the major underlying causes of cancers are environmental in nature. Apart from genetic factors, food and nutrition are important modifiers of cancer risk..Studies of immigrants in various parts of the world support the concept that many human cancers arise from interaction between the environment and constituents of the cells and their membranes. In the past, the concept of etiology of cancer has generally focused on four agents: viruses, radiation, chemical carcinogens and environmental pollutants. Currently, it is estimated that environmental factors are primarily responsible for a significant percent of all human cancers [13].Some of these factors include exogenous chemicals, tobacco smoke and a number of dietary constituents. During the 1930's and 1940's, a number of studies showed repeatedly that diet modification in experimental animals exposed to chemical carcinogens resulted in a beneficial effect [14].During this interval, it was shown that dietary constituents such as vitamins and anti-oxidants had a modifying effect in experimental cancers. Humans are continuously exposed to a variety of carcinogens in their immediate environment. These include carcinogens in the smoke, alcoholic beverages, industrial carcinogens such as asbestos and several non-essentials dietary constituents. The compounds found in diet that are known to be carcinogens include aflatoxins, heterocyclic amines, N-nitroso compounds and similar chemicals and polycyclic aromatic hydrocarbons. With the current advances in transportation and export, it is common to find food articles cultivated throughout the world in most parts of the world. In the fast growing countries, many chemicals and fertilizers are extensively used to increase the food production. When such products are exported to industrialized countries, there is additional risk for the intake of dietary components containing carcinogens and toxic residues even in affluent countries. Carcinogens, heavy metals and toxic residues are known to damage DNA in several ways and that detoxification can be a possibility at the early stage in the metabolic pathway. The efficacy of detoxification can be vital in determining the carcinogen potency. Dietary intervention is probably one way of influencing the carcinogen metabolism.

damaging effect of free radicals (ROS) are encountered by enzymes and small molecules such as glutathione, acetycysteine and uric acid. Certain vitamins like carotene deriva‐ tives, minerals and certain trace elements may also counteract the action of free radicals [23]. Under normal circumstances, the defense systems in the body work efficiently and balance the oxidants produced in the cells during various metabolic activities. When oxidant stress is increased, additional antioxidants may be required. The most important antioxi‐ dant enzymes are superoxide dismutase, catalase and peroxidases. Among the micronu‐ trient antioxidants, the important ones are vitamin C, Vitamin E, beta–carotene and the essential trace element selenium. The richest source of these nutrients is fresh fruits, vegetable oils, nuts and grain. Most plants contain phytochemicals such as flavanoids and polyphenols. A number of experimental studies have shown that they have antioxidant activities. Flavanoids are water soluble pigments found in exotic fruits, seeds, leaves and bark. These pigments can scavenge reactive oxygen species and thus can prevent break‐ ing lipid peroxide chain reactions.According to Carmia, experimental studies show that the phytochemicals can protect cells from ionizing radiation, inhibit mutations and block prostaglandin synthesis and thus prevent multistage carcinogenesis [16]. Polyphenols found in green tea and grapes have greater antioxidant potential than that exerted by vitamin C and E [17]. Ellagic acid is a phenol found in grapes, various berries and it has been found to protect liver toxicity leading to cancer. Garlic, onions, shallots and leeks also contain several natural antioxidants including flavanoids, vitamin C, selenium and sulfur com‐ pounds that increase the metabolic disposal of chemical carcinogens. In recent years, it has been reported that dark chocolate and red wine also contains phytochemicals and may scavenge reactive oxygen species [18]. With the increased pollution of the environment, it is likely that many of these useful components in plant materials may decrease, especial‐

Dietary Aspects in Cancer Prevention — A Mini-Review

http://dx.doi.org/10.5772/57371

183

Until recently, scientists engaged in the study of aging thought that the ROS played a crucial role in aging process. Now, the theory of aging due to oxidative damage is being re‐ placed by other factors. Over the course of past few years, many experiments designed to further support the idea that the ROS and other reactants drive aging have shown very challenging and controversial results. What these results show is that under certain situations, the high energy ROS may not be dangerous but useful and healthy. A final proof, however, for the beneficial effect of free radicals is currently lacking. It is hard to imag‐ ine that antioxidants will ever fall out of favor completely. As mentioned earlier, the amounts of natural antioxidants found in plant material, fruits and nuts ought to have a beneficial effect from en evolutionary point of view. There are millions of people in countries like India who survive mainly on food-stuffs of vegetable origin. So are many other species thriving in the forests. Nature must have designed its own mechanisms to deal with

Table 3 shows a list of various dietary components that have shown to have some beneficial

ly in fast-growing countries.

environmental factors that influence health and disease.

against detoxification of chemical carcinogens.

Food-stuffs containing large amounts of plant materials are good sources of a number of bioactive components. Such compounds and their derivatives are shown to inhibit carcino‐ genesis in a number of experimental systems involving initiation, promotion and progression. The role of diet in the final carcinogenesis is, however, not very clear at present. Recent studies show that many carcinogens and tumor promoters can produce reactive oxygen species (ROS) that can induce DNA damage and consequent chromosomal breakage. Dietary carcinogens mentioned earlier along with the cooking process and spoiled foods can add further to the body´s carcinogen load. If diets are rich in fruits and vegetables, some of these carcinogens may be detoxified before they become bioactive. During the second stage of cancer develop‐ ment, restriction of energy intake and increased physical activity may have some additional beneficial effect. In the final stage of tumor development when DNA damage plays a crucial role, the amount of single nutrients such as folate, zinc and selenium are known to play some role in the prevention of chromosomal damage and DNA methylation.

### **4. Reactive oxygen species, antioxidants and cancer prevention**

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and includes both genetic and biochemical changes in the cells. DNA strand breaks are one such injury. Agents that induce DNA damage, and thereby cause cancer include ionizing radiation, ultraviolet light, tobacco smoke, ozone and oxides of nitrogen in the polluted air. As mentioned earlier, reactive oxygen species (ROS) is known to cause damage to the DNA and it is very likely that the carcinogens mentioned above produce cell damage through the action of reactive oxygen species. It is also known that the

damaging effect of free radicals (ROS) are encountered by enzymes and small molecules such as glutathione, acetycysteine and uric acid. Certain vitamins like carotene deriva‐ tives, minerals and certain trace elements may also counteract the action of free radicals [23]. Under normal circumstances, the defense systems in the body work efficiently and balance the oxidants produced in the cells during various metabolic activities. When oxidant stress is increased, additional antioxidants may be required. The most important antioxi‐ dant enzymes are superoxide dismutase, catalase and peroxidases. Among the micronu‐ trient antioxidants, the important ones are vitamin C, Vitamin E, beta–carotene and the essential trace element selenium. The richest source of these nutrients is fresh fruits, vegetable oils, nuts and grain. Most plants contain phytochemicals such as flavanoids and polyphenols. A number of experimental studies have shown that they have antioxidant activities. Flavanoids are water soluble pigments found in exotic fruits, seeds, leaves and bark. These pigments can scavenge reactive oxygen species and thus can prevent break‐ ing lipid peroxide chain reactions.According to Carmia, experimental studies show that the phytochemicals can protect cells from ionizing radiation, inhibit mutations and block prostaglandin synthesis and thus prevent multistage carcinogenesis [16]. Polyphenols found in green tea and grapes have greater antioxidant potential than that exerted by vitamin C and E [17]. Ellagic acid is a phenol found in grapes, various berries and it has been found to protect liver toxicity leading to cancer. Garlic, onions, shallots and leeks also contain several natural antioxidants including flavanoids, vitamin C, selenium and sulfur com‐ pounds that increase the metabolic disposal of chemical carcinogens. In recent years, it has been reported that dark chocolate and red wine also contains phytochemicals and may scavenge reactive oxygen species [18]. With the increased pollution of the environment, it is likely that many of these useful components in plant materials may decrease, especial‐ ly in fast-growing countries.

human cancers [13].Some of these factors include exogenous chemicals, tobacco smoke and a number of dietary constituents. During the 1930's and 1940's, a number of studies showed repeatedly that diet modification in experimental animals exposed to chemical carcinogens resulted in a beneficial effect [14].During this interval, it was shown that dietary constituents such as vitamins and anti-oxidants had a modifying effect in experimental cancers. Humans are continuously exposed to a variety of carcinogens in their immediate environment. These include carcinogens in the smoke, alcoholic beverages, industrial carcinogens such as asbestos and several non-essentials dietary constituents. The compounds found in diet that are known to be carcinogens include aflatoxins, heterocyclic amines, N-nitroso compounds and similar chemicals and polycyclic aromatic hydrocarbons. With the current advances in transportation and export, it is common to find food articles cultivated throughout the world in most parts of the world. In the fast growing countries, many chemicals and fertilizers are extensively used to increase the food production. When such products are exported to industrialized countries, there is additional risk for the intake of dietary components containing carcinogens and toxic residues even in affluent countries. Carcinogens, heavy metals and toxic residues are known to damage DNA in several ways and that detoxification can be a possibility at the early stage in the metabolic pathway. The efficacy of detoxification can be vital in determining the carcinogen potency. Dietary intervention is probably one way of influencing the carcinogen

182 Pharmacology and Nutritional Intervention in the Treatment of Disease

Food-stuffs containing large amounts of plant materials are good sources of a number of bioactive components. Such compounds and their derivatives are shown to inhibit carcino‐ genesis in a number of experimental systems involving initiation, promotion and progression. The role of diet in the final carcinogenesis is, however, not very clear at present. Recent studies show that many carcinogens and tumor promoters can produce reactive oxygen species (ROS) that can induce DNA damage and consequent chromosomal breakage. Dietary carcinogens mentioned earlier along with the cooking process and spoiled foods can add further to the body´s carcinogen load. If diets are rich in fruits and vegetables, some of these carcinogens may be detoxified before they become bioactive. During the second stage of cancer develop‐ ment, restriction of energy intake and increased physical activity may have some additional beneficial effect. In the final stage of tumor development when DNA damage plays a crucial role, the amount of single nutrients such as folate, zinc and selenium are known to play some

role in the prevention of chromosomal damage and DNA methylation.

**4. Reactive oxygen species, antioxidants and cancer prevention**

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and includes both genetic and biochemical changes in the cells. DNA strand breaks are one such injury. Agents that induce DNA damage, and thereby cause cancer include ionizing radiation, ultraviolet light, tobacco smoke, ozone and oxides of nitrogen in the polluted air. As mentioned earlier, reactive oxygen species (ROS) is known to cause damage to the DNA and it is very likely that the carcinogens mentioned above produce cell damage through the action of reactive oxygen species. It is also known that the

metabolism.

Until recently, scientists engaged in the study of aging thought that the ROS played a crucial role in aging process. Now, the theory of aging due to oxidative damage is being re‐ placed by other factors. Over the course of past few years, many experiments designed to further support the idea that the ROS and other reactants drive aging have shown very challenging and controversial results. What these results show is that under certain situations, the high energy ROS may not be dangerous but useful and healthy. A final proof, however, for the beneficial effect of free radicals is currently lacking. It is hard to imag‐ ine that antioxidants will ever fall out of favor completely. As mentioned earlier, the amounts of natural antioxidants found in plant material, fruits and nuts ought to have a beneficial effect from en evolutionary point of view. There are millions of people in countries like India who survive mainly on food-stuffs of vegetable origin. So are many other species thriving in the forests. Nature must have designed its own mechanisms to deal with environmental factors that influence health and disease.

Table 3 shows a list of various dietary components that have shown to have some beneficial against detoxification of chemical carcinogens.


show that rather than causing aging, some ROS may prove beneficial. One possibility is that certain number of ROS stimulates an organism´s internal repair mechanism to get to work. In genetically modified roundworms which produced high levels of certain ROS, it was observed that these worms lived much longer than the normal worms. And further, when these worms were fed with antioxidants, their longevity advantage disappeared. In the February issue of The Scientific American this year, Melinda Moyer has summarized the results of recent studies and her title of her article is "The Myth of Antioxidants" [25].

Dietary Aspects in Cancer Prevention — A Mini-Review

http://dx.doi.org/10.5772/57371

185

It appears that the final verdict about the role of ROS in aging and cancer and the beneficial effect, if any, of antioxidants is yet to come. In most developed countries, the consumption of antioxidants as OTC products is very high. These antioxidants include Vitamin E, betacarotene and Vitamin C. As mentioned earlier, epidemiological studies show that people who eat lots of fruits and vegetables, which are rich in these antioxidants, tend to live longer and are less likely to develop cancer compared to those who eat normal diets. So, it seemed obvious that supplementing daily diets with antioxidants should lead to a better life. But the results of the most rigorously designed studies do not support that hypothesis, Indeed, the evidence shows that some people who take certain vitamin supplements are actually more likely to develop life-threatening illnesses such as lung cancer and heart disease [18]. The influence of mass media is one reason for the high consumptions vitamins and antioxidants. We need more studies and further proof to establish the relation between ROS and antioxidants. Until that

Many of the minerals and trace elements are nutrients that cannot be synthesized by the body. They are involved in all phases of cellular metabolism in one way or another. Trace elements are integral parts of very many enzymes including the ones that scavenge ROS.The minerals and trace elements that are of interest include calcium (together with vitamin D), magnesium, iodine, iron, selenium and zinc. Evidence suggesting the relationship of other minerals and toxic heavy metals with cancer is not substantial and as such, they are not described in this review. The dietary intake of minerals and trace elements in various parts of the world vary significantly due to varied eating habits, culture and tradition, climatic conditions and the amount present in the soil. Studies by the current authors indicate that the intake of a number of important trace elements and minerals is below the current recommended levels [18].The intake levels are especially low in the elderly [18].The richest source of calcium is dairy products and fish. Selenium levels in the soil vary greatly in different regions of the world. Australia, New Zealand and Scandinavian countries have low selenium levels in the soil. Selenium is mainly found in meat, fish and certain cereals [18].Hem iron is mainly found in foods of animal origin. Non-hem iron is found in plant foods and legumes. Zinc is rich in seafood, meat and unprocessed vegetable material. Oysters are one of the richest sources of zinc. Modern food processing destroys significant amounts of trace elements than found in

time, we have to cope with controversy about ROS, aging. and cancer.

the natural material. For iodine, the best sources are sea food and seaweed.

**5. Minerals and trace elements**

**Table 3.** List of selected nutrients that have antioxidant potential

As can be seen from table 3, a large number of constituents in fruits, vegetables, green tea, grapes, pepper, red wine and salmon possess substances that have anticancer potential. Apart from the carcinogen exposure from the immediate environment, a number of substances in cooked, grilled and smoked meat can contribute to the carcinogenic load of the cells in the body. The extents to which such carcinogens induce cancer development depend on the quality and quantity of the food consumed regularly and the concentration of scavengers available during the metabolism of cells. During the intermediate stage of cancer development, the restricted energy intake and increased physical activity can have significant additive effect on cancer development through the action of hormones and growth factors.

Reactive oxygen species are also known to be associated with aging process in a number of species, including humans. It is a common observation that the prevalence of many human cancers is high in aging populations. Average life-span in most developed coun‐ tries as well as in many fast-growing developing countries in Asia, Africa and Latin America has increased tremendously during the last few decades. According to several research groups, cellular damage caused by oxidation is one of the main mechanisms of aging. According to this theory, rampant oxidation in the cells mangles more and more lipids, proteins, and snippets of DNA and other key components of cells over time, eventually compromising tissues and organs and thus resulting in organ failure. Recent studies, however, showed that increase in certain free radicals in mice and worms correlate larger life span. Indeed, in some circumstances, reactive oxygen species seem to signal cellular repair methods. Experimental studies by several groups in the United States of America show that rather than causing aging, some ROS may prove beneficial. One possibility is that certain number of ROS stimulates an organism´s internal repair mechanism to get to work. In genetically modified roundworms which produced high levels of certain ROS, it was observed that these worms lived much longer than the normal worms. And further, when these worms were fed with antioxidants, their longevity advantage disappeared. In the February issue of The Scientific American this year, Melinda Moyer has summarized the results of recent studies and her title of her article is "The Myth of Antioxidants" [25].

It appears that the final verdict about the role of ROS in aging and cancer and the beneficial effect, if any, of antioxidants is yet to come. In most developed countries, the consumption of antioxidants as OTC products is very high. These antioxidants include Vitamin E, betacarotene and Vitamin C. As mentioned earlier, epidemiological studies show that people who eat lots of fruits and vegetables, which are rich in these antioxidants, tend to live longer and are less likely to develop cancer compared to those who eat normal diets. So, it seemed obvious that supplementing daily diets with antioxidants should lead to a better life. But the results of the most rigorously designed studies do not support that hypothesis, Indeed, the evidence shows that some people who take certain vitamin supplements are actually more likely to develop life-threatening illnesses such as lung cancer and heart disease [18]. The influence of mass media is one reason for the high consumptions vitamins and antioxidants. We need more studies and further proof to establish the relation between ROS and antioxidants. Until that time, we have to cope with controversy about ROS, aging. and cancer.
