Roles of fruits and vegetables in cancer therapy

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Roles of fruits and vegetables in cancer therapy

Introduction

Fruit and vegetables are high in nutrients that are potentially protective against cancer. They also play an important role in weight management. As obesity is a known risk factor for cancer of the colon, breast (in post-menopausal women),endometrium, kidney and oesophagus, fruit and vegetables may also protect against cancer indirectly by helping to maintain a healthy body weight. Although there has been a slight weakening of the evidence supporting the role of fruit and vegetables in reducing the risk of some cancers, overall the evidence is suggestive of a protective effect. Recent studies show that fruit and vegetables are protective against oral, laryngeal, oesophageal, colorectal and lung cancers.The association of fruit and vegetable consumption on stomach cancer risk remainsin conclusive, however fruit may possibly be protective. Fruit consumption also appears to provide protection against bladder cancer.Fruit and vegetable consumption does not appear to be associated with a lower risk of prostate, breast or ovarian cancer. However, one meta-analysis suggests that tomato consumption may reduce the risk of prostate cancer.The Cancer Council supports that recommend eating plenty of fruit and vegetables, and the population recommendation of at least two serves of fruit and five serves of vegetables daily.Because the knowledge is still incomplete about the ways in which nutrients may reduce cancer risk, The Cancer Council also recommends that people eat a variety of different fruit and vegetables to obtain maximum benefits. Fruit and vegetables are best consumed fresh and whole (i.e. not in a supplement form) and consumption of both cooked and raw vegetables are recommended. For people already diagnosed with cancer, there is some evidence that a diet high in fruit and vegetables is not of significant benefit, but is unlikely to be harmful. The Cancer Council recommends the general community guidelines of two serves of fruit and five serves of vegetables daily for cancer survivors. Because the knowledge is still incomplete about the ways in which nutrients may reduce cancer risk, The Cancer Council also recommends that people eat a variety of different fruit and vegetables to obtain maximum benefits. Fruit and vegetables are best consumed fresh and whole (i.e. not in a supplement form) and consumption of both cooked and raw vegetables are recommended.

1.1.Background

The International Agency for Research on Cancer (IARC) concluded that 5-12% of cancers could be attributed to low fruit and vegetable consumption.¹ Australian data suggests that 2% of cancers were attributable to low consumption of fruit and vegetables.² In terms of health care costs, it has been estimated that low vegetable intake (<4 serves per day) accounts for 17% of the cost of bowel cancer, 2% of the cost for breast cancer, and 9% of the cost of lung and of prostate cancer.³ Twenty one percent of the cost of lung cancer and 4% of the cost of breast cancer has been attributed to lower fruit intake (<3 serves per day).³The protective effects of fruit and vegetables against cancers, as well as other diseases such as coronary heart disease and type 2 diabetes, has led to the promotion of fruit and vegetables consumption as a national public health priority.⁴Fruit and vegetables also play an important role in weight management due to their low energy density, high fibre content and capacity to displace higher energy foods from the diet. Obesity is a known risk factor for cancer of the colon, breast (in postmenopausal women), endometrium, kidney and oesophagus.⁵ Emerging evidence suggests that obesity is also linked to cancer of the pancreas, gallbladder, thyroid, ovary and cervix as well as non-Hodgkin’s lymphoma and multiple myeloma.⁶ Therefore fruit and vegetables may reduce the risk of cancer directly through the provision of specific anti-carcinogenic agents and indirectly through their role in weight management.

1.2.The Impact of Diet on the Development of Cancer

Dietary factors may account for approximatively 35% of cancer death, similar to the impact of smoking⁷. Such a close relationship between diet and cancer is well illustrated by the large variations in rates of specific cancers among countries as well as by the spectacular changes observed in the cancer incidence rates in migrating populations⁸. Among specific aspects of the diet that are the most closely associated with cancer, a large number of ecological, case-control and cohort epidemiological studies have consistently associated increased consumption of fruits and vegetables with a decreased risk for a wide variety of cancer, particularly those of epithelial origin⁹. In these studies, people consuming the least fruit and vegetables are about two-fold more susceptible to develop some cancers than those having the highest consumption of these foods. These studies thus suggest that fruits and vegetables represent an essential source of molecules with chemopreventive properties, an hypothesis strengthened by many experimental data obtained using cellular and animal models in which molecules isolated from several food sources were found to induce tumor cell death as well as to reverse the development of several cancers¹⁰ .

2. Fruits and Vegetables are an Important Source of Anticancer Agents

Fruit and vegetables are high in nutrients that are potentially protective against cancer. Anti-carcinogenic activity may be provided by nutrients such as fibre, vitamins, minerals, antioxidants and phytochemicals, which are chemicals found in plants such as flavonoids, carotenoids and lignans. It is probably a combination of these nutrients and phytochemicals found together in whole foods that helps to reduce the risk of chronic diseases rather than one anti-cancer component, although many different mechanisms have been proposed¹¹.Single nutrients identified from the analysis of epidemiological studies have usually been unsuccessful when investigated further in trials, making the whole food approach more appropriate to prevention advice.Fruit and vegetables in particular have attracted much research attention for their cancer protective effects, and accordingly, many cancer associations worldwide, together with a number of National Dietary Guideline committees have recommended a daily intake of 5-7 serves of fruits and vegetables to reduce cancer risk. In spite of considerable evidence linking the consumption of fruits and vegetables to a reduction of cancer risk, the identification of the biologically active molecules that are responsible for the chemopreventive properties of these foods is still a matter of intensive investigation.Research carried out during the last years has shown that fruits and vegetables arerich sources of phytochemicals, non-nutritive molecules that play essential roles in various aspects of plant physiology, especially in their defense mechanisms against insects and various microorganisms. A wide variety of phytochemicals have been described to date and are classified by protective function, physical characteristics and chemical characteristics. The three major classes of phytochemicals are the polyphenols (flavonoids, isoflavones, anthocyanins, catechins, etc.), terpenes (including the subclasses carotenoids and limonoids) and the thiols (including the subclasses indoles, dithiolthiones and isothiocyanates).These molecules are responsible for most of the color, odor and astringency of fruits and vegetables, and are present in significant amounts in plant-based foods : a daily intake of a mixture of fruits, vegetables and drinks such as green tea and red wine contains about 1 to 2 g of these phytochemicals, corresponding to the ingestion of about 5,000 to 10,000 different compounds¹².One of the best characterized biological activity of phytochemicals is their antioxidant properties¹³. For example, a medium-sized apple, which contains 10 mg of vitamin C has an antioxidant potential similar to that of 2350 mg of this vitamin¹⁴, a property mostly due to its high content in polyphenols such as flavonoids and procyanidins¹⁵. However, although the antioxidant properties of phytochemicals have recently received enormous attention, there is concluding evidence that these compounds possess several additional anticancer properties that play crucial roles in the chemopreventive properties of fruits and vegetables ^(16;17).

2.1. How do Fruits and Vegetables Prevent Cancer?

The recognition of fruits and vegetables as a source of anticancer molecules has led to considerable interest in the identification and characterization of the mechanisms by which naturally occurring phytochemicals found in the diet are capable of inhibiting,retarding or reversing carcinogenesis¹⁶. To date, at least four major mechanisms have been proposed to account for the chemopreventive properties of phytochemicals:

2.1.1. Stimulation of the Host’s Defense Mechanisms against DNA Damaging Events. A number of factors can induce damage to DNA and initiate cancer. Free radicals, environmental or diet-associated chemicals, UV irradiation or some viruses all have the capacity to cause significant damage to the cells that may ultimately lead to cancer¹⁸. Most, if not all environmental carcinogens are metabolized once they enter the body by the so-called Phase I metabolism, a physiological reaction primarily catalyzed by the cytochrome P450 enzymes¹⁹. However, this reaction often converts procarcinogens into highly reactive chemical intermediates that can bind and alter the function of key cellular macromolecules such as DNA. A second group of enzymes, known as Phase II enzymes, conjugate these recative intermediates with a number of endogenous factors, resulting in the production of water-soluble products that can be excreted by the body ²⁰.There is considerable evidence that several chemopreventive phytochemicals elicit their anticancer effects by modulating these enzymatic systems, either by reducing their carcinogenic potential (through the inhibition of the Phase I enzymes) or by increasing the excretion of the carcinogens, through increase of Phase II enzymes activity²⁰. The most well-documented example of such a mechanism of action is theremarkable anticarcinogenic activity of isothiocyanates, compounds that are found in high amounts in cruciferous vegetables. Isothiocyanates inhibit tumorigenesis induced by a wide variety of chemical carcinogens, this effect being related to their reduction of genetic damage as a result of the inhibition of Phase I enzymes and activation of Phase II enzymes²¹. A number of phytochemicals that modulate the host’s defense mechanism against DNA-damaging molecules are also found in several other fruits and vegetables, including garlic and its related members of the Allium family, as well as citrus fruits. The presence of these biologically molecules causing the reduction of the oncogenic potential represents an efficient first-line defense against cancer that certainly contribute to the chemopreventive properties of fruits and vegetables.

2.1.2. Cytoxicity against Tumor Cells. In vitro experimental systems using cells isolated from various human tumors are being widely used to study the anticancer properties of dietary-derived phytochemicals. A large number of molecules have been shown to cause significant damage to cancer cells, leading to growth arrest and, in several cases, to the induction of apoptosis. Of particular interest is the strong proapoptotic activity of several isothiocyanates from cruciferous vegetables, such as phenethyl isothiocyanate (PEITC)²², as well as the potent cytotoxic effect of curcumin against several tumor cell lines²³. How these cytotoxic properties contribute to the chemopreventive effects of these phytochemicals remains unclear but could play an essential role by preventing the growth of cells that have already acquire an initiated phenotype (precancerous cells).

2.1.3. Antiangiogenic Properties. Tumor angiogenesis, the process by which tumor cells stimulate the formation of a new blood vessel network that is necessary for their growth and progression, plays an essential role in tumor growth²⁴. As a consequence, inhibition of angiogenesis has been proposed to represent an effective mean to interfere with tumor progression, leading to extensive efforts aimed at the identification of antiangiogenic molecules²⁵. Interestingly, many phytochemicals have recently been shown to possess strong antiangiogenic activities²⁶.For example, an abundant polyphenol found in green tea, epigallocatechin gallate (EGCG), was found to potently inhibit a crucial receptor involved in angiogenesis (VEGFR-2), this inhibitory effect occurring at concentrations readily achievable by the consumption of moderate amounts of green tea²⁷. This inhibitory effect is not restricted to green tea catachins since a potent VEGFR inhibitory activity was also recently identified for delphidin, an abundant blueberry anthocyanidine³⁶. In a similar manner, ellagic acid, a phenolic acid found in high quantities in some fruits, such as raspberries and strawberries, also interfere with VEGFR-2 and also strongly inhibits the activity of another receptor found in perivascular cells, PDGFR²⁸. This combined inhibitory effect of receptor tyrosine kinases that are both essential for angiogenesis leads to the inhibition of angiogenesis in both in vitro and in vivo assays ^(27,28). As will be discussed in more details below, there is increasing evidence that the antiangiogenic effects of these phytochemicals may play a crucial role in the chemopreventive effect of these molecules.

2.1.4. Increase in Intestinal Absorption or Inhibition of Hepatic Metabolism. Another manner by which dietary-derived phytochemicals may influence tumor progression involve an indirect mechanism, in which a given molecule, with little intrinsic anticancer property, may greatly influence the biodisponibility of another phytochemical with potent anticancer activity. Perhaps the best example of this indirect synergistic mechanism is the effect of piperine, a black pepper component, on the serum concentration of curcumin. In the absence of piperine, curcumin is poorly absorbed and rapidly excreted. However, when co-administered with piperine, the absorption of curcumin is increased about a thousand-fold²⁹, an effect possibly related to the modulation of intestinal proteins, such as P-gp and CYP3A4, both involved in the metabolism ofxenobiotics³⁰.

2.2. Views on Fruit and Vegetables in Cancer Prevention Reports

Several major reports that have investigated the relationship between fruit and vegetable intake and cancer risk show that there has been a shift in the strength of the evidence over the last 10 years. These reports indicate that the evidence appears to be somewhat weaker than previously thought (Table 1). On the whole,evidence that vegetables are protective is stronger than for fruits, but this may simply reflect the generally greater consumption of vegetables worldwide or the different mix of nutrients obtained from them.

Table 1: Conclusions from the major cancer prevention reports regarding the cancer protective effect of fruit (f) and vegetables (v)

Organisation Review	Highest Evidence Convincing	Moderate Evidence Probable	Lower Evidence Possible
WCRF/AICR (1997)31	Mouth (f&v) Pharynx (f&v) Oesophagus (f&v) Stomach (f&v) Colon & rectum (v) Lung (f&v)	Larynx (f&v) Pancreas (f&v) Breast (f&v) Bladder (f&v)	Ovaries (f&v) Cervix (f&v) Endometrium (f&v) Thyroid (f&v) Liver (v) Prostate (v) Kidney (v)
COMA (1998)32	Oesophagus (f&v)	Stomach (f&v) Colon & rectum (v)	Breast (f&v)
WHO/FAO (2003)33		Oral Cavity (f&v) Oesophagus (f&v) Stomach (f&v) Colon & rectum (f&v)
IARC (2003)1		Oesophagus (f&v) Stomach (f) Colon & rectum (v)	Mouth (f&v) Pharynx (f&v) Larynx (f&v) Kidney (f&v) Colon and rectum (f) Bladder (f) Stomach (v) Lung (v) Ovary (v)

In 1997, the World Cancer Research Fund and the American Institute of Cancer Research (WCRF/AICR) jointly published an extensive, global review of the role of food and nutrition in the prevention of cancer.8 The conclusions by WCRF/AICR relating to the protective effect of fruits and vegetables can be seen in Table 2.Many of the views expressed in the 1997 WCRF/AICR report were also reflected inan extensive review published the previous year,which found that fruit and vegetables appeared to protect against cancer of the mouth, pharynx, oesophagus,stomach, colon, pancreas, endometrium and lung³⁴.This review also noted that vegetables in general, and raw vegetables in particular, appear to be the outstanding protective categories³⁴.They specifically identified allium vegetables (including onions, garlic and leeks), carrots, green vegetables in general, cruciferous vegetables (such as cabbage, cauliflower, broccoli, brussel sprouts, Chinese cabbage and bok choy) and tomatoes as strongly protective.

Table 2: WCRF/AICR conclusions relating the cancer protective effect of particular types of fruits and vegetables³¹.

Fruit or Vegetable	Convincing	Probable	Possible
Vegetables	Colon		Prostate Liver Kidney
Cruciferous vegetables		Colon & rectum Thyroid
Allium vegetables	Stomach		Colon
Green vegetables	Lung		Oesophageal Colon Breast
Green leafy vegetables	Stomach	Mouth/oral Pharyngeal
Raw Vegetables	Stomach
Tomatoes	Stomach		Lung
Carrots		Stomach Lung Bladder	Mouth/oral Rectum
Citrus fruits	Stomach		Mouth/oral Oesophageal

The United Kingdom Department of Health Committee of the Medical Aspects of the Food Supply (COMA) reviewed the evidence concerning the potential protection afforded by fruit and vegetables against the development of cancer in 1998 ³².No strong association was found between fruit and vegetable consumption and cancer at any site, while a moderate association was noted for cancers of the stomach, colon and rectum (Table 1). This is in contrast to WCRF/AICR, who rated the evidence of an association for cancer of the mouth, pharynx, stomach, colon, rectum and lung as convincing (Table 1). Although they did not agree on the strength of evidence for each, these two major international organisations did agree that increased consumption of fruits and vegetables is associated with a reduced risk for cancers of the oesophagus, stomach, colon, rectum and breast (Table 1). The different conclusions reached in the WCRF/AICR and COMA reports relate to their relative weighting of different types of evidence. In the 1998 COMA report, prospective cohort studies carried more weight than case control or ecological studies, and mechanistic studies of induced tumours in standard animal models were not included. In 1997, the WCRF/AICR expert review panel examined in vitro studies and animal trials as well as ecological, case-control and cohort studies in human populations. At the time of the WCRF report, there were only a limited number of cohort studies that had reported on fruit and vegetable intake and cancer risk. Results published in 2001 from the EPIC study showed that significant health gains are made from even a small increase in fruit and vegetable intake³⁵. Increasing intakes of fruit and vegetables by just 50g a day (equivalent to 2/3 cup cooked vegetables or 1/3 of a piece of fruit) was associated with a reduction in cancer risk of around 20% ³⁵. In 2003, The World Health Organisation (WHO) suggested that a high intake of fruit and vegetables probably reduces the risk of cancers of the oral cavity, oesophagus,

stomach and colorectum (Table 1)³³. WHO recommended an intake of at least 400g of fruit and vegetables daily (in addition to potatoes). However, they found that support for a broad and strong protective effect of higher vegetable and fruit intake had weakened with results from recent prospective studies. Similarly, IARC found that a high intake of vegetables probably reduces the risk of oesophageal and colorectal cancer, while a high intake of fruit probably reduces the risk of oesophageal and stomach cancer (Table 1)¹. However the IARC rated the evidence for an association between vegetable intake and cancer of the mouth, pharynx, larynx, kidney, stomach, lung and ovary and the evidence for an association between fruit intake and cancer of the mouth, pharynx, larynx, kidney, colorectum and bladder as possible¹.The conclusions from WHO and IARC differ from the previous reviews by WCRF/AICR and COMA because of the inclusion and consideration of more prospective studies published since these original reviews were undertaken. In recent years it has been increasingly apparent that the protective association between fruit and vegetable intake and cancer is much stronger in case-control studies than in cohort studies. Furthermore, randomised controlled trials involving fruit and vegetable intake, notably for colorectal cancer, have not demonstrated any benefit. Case-control studies are known to be prone to recall and selection bias, however the length of follow-up in cohort studies can also potentially limit the interpretation of their results. In 2004, the IARC reviewed the evidence relating to cruciferous vegetables, isothiocyanates and indoles and found that for human studies³⁶:

• There is limited evidence that eating cruciferous vegetables reduces the risk for cancers of the stomach and lung.
• There is inadequate evidence that eating cruciferous vegetables reduces the risk for cancers at all other sites.

• There is inadequate evidence to assess the independent effects on human.

cancer risk of isothiocyanates and indoles, as opposed to their combined effects with other compounds in cruciferous vegetables. The recent evidence supporting a direct role for fruit and vegetables in cancer prevention appears to be mixed. In 2007, WCRF will publish an update of their conclusions regarding fruit and vegetables in their Report on Food, Nutrition Physical Activity and the Prevention of Cancer. The report will review all the available science relating to cancer prevention. It is hoped that this report will further clarify the role of fruit and vegetables in cancer prevention. In the meantime, The Cancer Council NSW has sought to review the recent

literature regarding the role of fruit and vegetables and cancer protection to help clarify the discrepancies that appear in the literature.

3. CANCER AT DIFFERENT SITES IN THE BODY

3.1. BREAST CANCER

WHO IS AT RISK?

Breast cancer is the second most common site of cancer in women (22%) with lung cancer incidence being 25%. It affects 1 out of 36 women in South Africa during their lifetime. Men can also get breast cancer, but this condition is very rare. As this disease is less well studied in men, this discussion is limited to breast cancer as seen in women. Breast cancer is the most common cause of death in women between the ages of 35 and 55 years. Breast cancer is thus a very important disease for women and the incidence of breast cancer in South Africa is increasing annually³⁷. The most recent statistics show that the incidence rate is 25 per 100 000. One million women are diagnosed with breast cancer per year worldwide; while an additional 1/2 million die of breast cancer every year.Within certain ethnic groups, breast cancer rates may double or triple over time and as they migrate and adopt new lifestyles. In formerly low-risk countries, such as Japan for instance, as the diet become more westernized the incidence of breast cancer increases. The same patterns of increases have been observed with migrants from low-risk to higher-risk areas, for example Japanese migrants to Hawaii. These patterns of change underscore the importance of the environment and nutrition in breast cancer risk.

WHAT CAUSES BREAST CANCER?

The exact cause of breast cancer is not clear yet, but it is known that certain risk factors are linked to the disease. Some risk factors, such as smoking, can be controlled, but others like a person’s family history, can’t be changed. While all women are at risk for breast cancer, the factors listed below can increase the chances of a woman developing the disease³⁸.

? Gender Women have a much greater risk of developing the disease than men.

? Age Risk increases with age.

? Race Caucasian women are slightly more at risk than black women, but black women are more likely to die of this cancer. Asian and Hispanic women have a lower risk. The incidence of breast cancer in Europe and the USA is 5 times more than in Japan and China.

? Family history Mother or sister affected.

Two first-degree family members

? Personal history

A woman with cancer in one breast has a greater chance of developing cancer in the other breast or in another part of the same breast. Certain types of previous abnormal biopsy results can be linked to a slightly higher risk as well.

? Exposure Radiation.

? Reproductive factors

Early menarche (before age of 12 years).Women who had no children or had their first pregnancy after the age of30.

Late menopause.

? Socio demographic factors

High income group.

High social class status.

Jewish religion.

? Birth control pills

It is still not clear what role birth control pills might play in breast cancer risk. A recent study found that women using birth control pills have a slightly higher risk and women who stopped using the pill for 10 years or more do not seem to have any increased risk. Women should discuss the risk and benefits of birth control pills with their doctor.

? Hormone replacement therapy

Long-term use (5 years or more) may slightly increase the risk. A woman’s breast cancer risk returns to that of the general population within 5 years of stopping the therapy.

? Physical activity

Low activity levels.

? DIETARY FACTORS:

Table 3: Dietary factors associated with a higher incidence of breast cancer

Weight gain (obesity)	Energy intake above the level that is needed daily is positively associated with breast cancer. There is an increased risk of breast cancer for women that are overweight, especially for women after menopause and those who do not use hormone replacement therapy. The connection between weight and breast cancer is complex. The risk seems to be higher for women who gained weight as adults, but not for those who have been overweight since childhood. Extra fat around the waist affects the risk more than the same amount of fat around the hips and thighs. The role of fat intake in weight gain is an important aspect to consider, as well as changes in metabolic rate, physical activity and overall dietary intake.
Dietary fat Intake	As a major contributor to total energy, dietary fat can also increase breast cancer risk. The importance of dietary fat as an influence independent of energy intake is however unclear.Some studies suggest that olive oil intake contributes to a lower breast cancer risk.
Alcohol Intake	Women who have 1 alcoholic drink per day have a small (11%) increased risk compared to those who have 2 drinks per day whom have 25% more risk compared to the risk of nondrinkers.
Fruit and Vegetables	High levels of consumption (more than 5 portions per day) have been associated with lower rates of breast cancer.
Other	Other dietary factors that may have an association with breast cancer risk are currently and continuously under study. Examples of other factors that might have an association with breast cancer rates include: Omega-3 fatty acids (fish oils), the active substances in fruit and vegetables (phyto-chemicals), vitamin A, vitamin D and xenoestrogens (soy products) may play a role in prevention of breast cancer.

3.2. PROSTATE CANCER

WHO IS AT RISK?

Cancer of the prostate gland is one of the most common fatal cancers and among the leading causes of cancer deaths in men over the age of 55.

RISK FACTORS OF PROSTATE CANCER

Following a typical western diet high in animal (saturated) fat is associated with a higher risk of prostate cancer. Excessive consumption of red meat has also been found to be positively associated with advanced prostate cancer³⁸.

Lycopene (the substance that provides the red colour in fruits and vegetables), found in foods such as tomato, tomato products, watermelon and red grapefruit, is associated with a reduced risk of prostate cancer as is Vitamin E supplementation³⁷.

3.3. GASTROINTESTINAL CANCERS

3.3.1. COLORECTAL CANCER

Colorectal cancer affects the colon and the rectum.

WHO IS AT RISK?

Excluding skin cancer, colorectal cancer ranks second after lung cancer in men, and breast cancer in women. It affects up to 6% of men and women by the age of 75 years in western societies.

RISK FACTORS FOR COLORECTAL CANCER

Cancer promoting dietary factors

Although many dietary factors have been associated with colon cancer, strong associations for an

increased risk have been reported with excessive consumption of red and processed meat (containing nitates, nitrites and nitrosamines, and made rich with heterocyclic amines during the cooking process) and high total fat intake. Overweight in men, and low levels of physical activity in men and women are linked with a higher risk, which has been found to increase with age. Excessive alcohol consumption has also been linked to an increased risk. The malnutrition associated with alcoholism is also likely to be important in the increased risk reported³⁸. More specifically, excessive beer consumption has been linked to an increased risk for colorectal cancer. It is thus wise to follow the recommendation of no more than 2 drinks per day for men and 1 for women. Patients with chronic ulcerative colitis have a high risk of developing colon cancer and frequently have low levels of folate. Folate supplements result in a 60% lower incidence of colon cancer in these patients.

Protective dietary factors

In terms of protective dietary factors, the frequent consumption of fruits and vegetables has been the most consistent in terms of preventive measures. In this regard, vegetarians are generally known to be at a lower risk. Although the predominant data available suggests that the intake of high-fiber foods protect the body from the development of colorectal cancer, many questions remain to be answered before this relationship can be clarified. Fruit and vegetables not only provide a high intake of dietary fiber, but also potentially protective phytonutrients³⁷. Furthermore, consuming diets rich in these sources also means displacing potentially cancer-promoting foods that are rich in energy and high in fat. The evidence for dietary fiber as being protective would appear to be less conclusive than that for a high consumption of fruit and vegetables. Other protective dietary factors implicated, but still under study, include folate, calcium, vitamin D, antioxidants and non-nutritive compounds in vegetables such as phyto-oestrogens and glucosinolates. The benefit of regular exercise in reducing the risk of colon cancer has been demonstrated in a number of studies.

3.3.2. OESOPHAGUS CANCER

RISK FACTORS

Studies have indicated that alcohol has a causal role in the development of cancer, especially for cancers of the mouth, pharynx and esophagus. It appears to have an increased effect on the tissues directly exposed to it during its consumption. The malnutrition associated with alcoholism is also likely to be important in the increased risk for certain cancers due to the lack of protective factors found in a varied diet. In this regard, such micronutrient deficiencies as niacin, riboflavin, zinc and selenium has been associated with this malignancy. Additionally, an association has been found between the drinking of very hot drinks, such as coffee and tea and the risk of esophageal cancer. Contamination of food by toxic substances takes place during charcoal broiling, frying and smoking of meats. An association has been found between an increased risk of esophageal cancer and the frequent intake of smoked and fried foods. Moreover, certain fungi (moulds), when present in foods, such as maize and wheat products are well known to produce toxins, known as mycotoxins. Mycotoxins have been found to cause a variety of ill effects in southern Africa, of which oesophageal cancer is one. A high consumption of fruit and vegetables are associated with a decreased risk³⁷.

3.3.3. STOMACH CANCER

WHO IS AT RISK?

After being the leading cause of cancer death worldwide until the 1980’s, stomach cancer has been declining since the 1960’s due to improvement in food storage and preservation and the recognition of other factors that play a major role in its development. Recent studies have shown that Helicobacter pylori infection results in lesions and ulcers of the stomach, thus producing conditions that promote cancer development in the stomach.

DIETARY FACTORS ASSOCIATED WITH STOMACH CANCER

An association has been found between an increased risk for stomach cancer and frequent intake of smoked, pickled and fried foods. Some studies have shown that a high salt intake also increases the risk. In terms of micronutrients, low blood levels of vitamin C are known to be associated with the progression of stomach cancer. A high consumption of fruit and vegetables appears to provide a protective effect. Emerging evidence also indicates that regular consumption of green tea may possibly reduce the risk of stomach cancer³⁸.

3.4. LUNG CANCER

WHO IS AT RISK?

Over the span of a century, lung cancer has changed from a rare disease to a leading cause of death.With the role of smoking in lung cancer well established, research has focussed primarily on environmental and genetic factors that can determine its risk.

RISK FACTORS FOR LUNG CANCER

Environmental and lifestyle factors:

• When smoking is stopped, lung cancer risk is still present even after 15-20 years of abstention, but not at the predicted high level of risk among those that continue to smoke.

• Exposure to environmental pollutants as well as occupational exposure to certain substances such as radon (found in underground mines), arsenic, asbestos, chromium, chloromethyl ethers, nickel and polycyclic aromatic hydrocarbons.

• Indoor air polluted with smoke from wood or coal burning and cooking fumes.

Dietary factors:

• Fruit and vegetables have repeatedly been shown to have a protective effect against lung cancer. The evidence for the protective effects of vegetables appears to be stronger than that for fruit.

• Fat intake is associated with lung cancer risk in men, but not women.

• Clinical trials done to test the hypothesis of the benefit of beta-carotene supplementation as a possible protective factor, particularly focussing on lung cancer, have shown that high dose betacarotene supplements are not beneficial in reducing cancer risk, and probably increase lung cancer risk among high-risk individuals such as those who smoke or those who have a history of occupational exposure to known lung carcinogens.

3.5. ORAL CANCER

A meta-analysis of 15 case-control studies and one cohort study found a statistically significant reduction in oral cancer risk for each portion of fruit (combined adjusted odds ratio (OR)= 0.51, 95% CI= 0.40-0.65) and vegetable consumed (combined adjusted OR= 0.50, 95% CI= 0.38-0.65).15 Similar results were found when results were pooled from 12 studies that adjusted for age, sex, smoking and alcohol intake (OR for fruit= 0.49, 95% CI= 0.39-0.63; OR for vegetables= 0.43; 95% CI= 0.31-0.59)³⁹. Interestingly citrus fruit appeared to provide greater protection than overall fruit consumption (OR= 0.38, 95% CI 0.26-0.56)^39. A meta-analysis completed in 2003 found that in case-control studies (nine studies on fruit and seven studies on vegetable consumption), both fruit (RR= 0.53, 95% CI= 0.37-0.76) and vegetables (RR= 0.84, 95% CI= 0.67-1.07) provided protection against oral cancer, with fruit providing a statistically significant result⁴⁰.

3.6. LARYNGEAL CANCER

In the only meta-analysis identified for laryngeal cancer, fruit consumption provided a significant protective effect (RR= 0.73, 95% CI= 0.64-0.84), while vegetables appeared to provide a very small non-significant reduction in risk (RR= 0.92, 95% CI= 0.83-1.02) in case-control studies (five studies on fruit and seven studies on vegetable consumption)⁴⁰. This meta-analysis was very limited, as out of the eight case-controls studies identified, one was excluded from the analysis on both fruit and vegetables, while two were excluded from the analysis on fruit. The authors point out that the first study was excluded because study subjects were classified into only two categories of consumption, however it is not known why the other two studies were excluded.

3.7. OVARIAN CANCER

In the only meta-analysis identified, total fruit and vegetable intake was not significantly associated with ovarian cancer risk⁴¹.Twelve cohort studies were included in this analysis. The pooled multivariate RR comparing the highest versus the lowest quartiles of intake showed little association for total fruit (RR= 1.11, 95% CI= 0.89-1.37) and total vegetable (RR= 0.88, 95% CI= 0.71-1.09) consumption with ovarian cancer cases that occurred within the first five years.25

When fruit and vegetable intake were represented as per 100g/day (which is approximately one serve per day), the RR values for total fruits, total vegetables and total fruits and vegetables had no association with ovarian cancer⁴¹.When grouped according to classes of fruit and vegetables, no statistically significant association was found. A marginally significant association with the consumption of green leafy vegetables for a 100g increment was found (pooled multivariate RR= 0.88, 95% CI=0.76-1.00)⁴¹.

3.8. BLADDER CANCER

Fruit consumption provided significant protection against bladder cancer (RR= 0.81, 95% CI= 0.73-0.91), which was consistent across five case-control (RR= 0.82, 95% CI= 0.70-0.94) and three cohort studies (RR= 0.80, 95% CI= 0.65-0.99)⁴⁰. Vegetable consumption showed a non-significant inverse association across all studies (RR= 0.91, 95% CI= 0.82-1.00), case-control (RR= 0.90, 95% CI= 0.78-1.03) and cohort studies (RR= 0.92, 95% CI= 0.75-1.14)¹.

4. Factors Reduce Risk of Cancer

Some of the major groupings of dietary factors associated with reduced risks of cancer are discussed below:-

4.1. Plant phenolics

The term plant phenols encompasses a wide variety of naturally occurring compounds which are

structurally related to the extent that they all contain one or more benzene rings, each with one or more hydroxyl group substitutions. Under this general rubric are included (1)the simple phenols eg gallic acid (tea), p-cresol (raspberry and blackberry, vanillin (vanilla); (2) the hydroxycinnamic acid derivatives, eg chlorogenic acid, a major component of coffee; and (3) the flavonoids including catechins from tea, anthocyanins which determine the colours of many flowers and fruits, and the ubiquitous flavones and flavonols.

In broad terms these substances are important for:-

• Their antioxidant properties, ie their ability to scavenge naturally occurring free radicals before they can damage macromolecules directly or indirectly involved in either cell proliferation (relevant to carcinogenesis) or lipid metabolism (relevant to cardiovascular disease).
• Blocking the formation of carcinogenic nitrosamines arising from the reaction of dietary

nitrates/nitrites with secondary amines and amides in the stomach.

• Their capacity to act as electrophile traps. In much the same manner in which they can scavenge nucleophilic free radicals, many plant phenols can also absorb highly reactive electrophiles thereby preventing damage to cellular components
• Inhibiting the generation of prostaglandins from arachidonic acid, and thereby retarding a ‘promotional’ phase of carcinogenesis.

4.2. Isothiocyanates

Cabbages, watercress and other cruciferous vegetables owe their sharp taste in part to isothiocyanates arising from the action of the enzyme myrosinase on glucosinolate conjugates. These isothiocyanates have been observed to inhibit chemically induced cancers in a variety of animal models. The mechanism involves the inhibition of the so-called Phase I enzymes whose normal function is to prepare foreign molecules for detoxification and excretion but which sometimes generate highly reactive intermediates capable of far more damage than the original substrates.

4.3. Phytoestrogens

There is still no agreement on how to define a phytoestrogen. In the context of this report any phytochemical which can substitute for, or block the action of, natural, endogenously produced steroid sex hormones may be regarded as a phytoestrogen. A recent definition of phytoestrogens as “plant derived compounds that can regulate gene expression that is mediated by an Estrogen Response Element, in a manner either comparable or apparently antagonistic to 17b-oestradiol, as a result of binding to the oestrogen receptor” ⁴², is too restrictive, and precludes a number of effects which are being increasingly linked in the literature with phytoestrogens. A confusing aspect of the usage of the term ‘phytoestrogenic’ is the fact that compounds to which this adjective is commonly applied may either mimic the effects of natural endogenous oestrogen, or they may block them and the same compound may be an agonist in one situation and an antagonist in others. A substance which is sufficiently similar to endogenous oestrogens to occupy an oestrogen binding site, but not sufficiently similar to reliably induce the event which normally ensues when natural oestrogen binds, would clearly be acting as an antagonist. However, when natural oestrogen is either absent, or present only in very low concentrations (postmenopausally, for example), the limited ability of a phytoestrogen to induce the secondary event may still be significant, and warrant its reclassification as an agonist. Given the epidemiologic evidence of an increasing risk of breast cancer with increasing cumulative oestrogen exposure it is perhaps not surprising that historically, our interest in the relevance of phytoestrogens to breast cancer stemmed from their ability to act as antagonists of oestradiol. Oestrogens should not just be linked with unfavourable long-term health outcomes, however. Premenopausally women have much more favourable risk factor profiles for cardiovascular disease than men – and this may be due to direct and indirect effects of oestradiol. There is also considerable contemporary interest in the potential for phytoestrogens, acting as oestrogen agonists, to alleviate the morbidity (eg hot flushes) associated with the cessation of oestradiol production at the menopause, and to slow or halt the bone-loss which can eventually lead to osteoporosis. Major classes of phytoestrogenic substances in the diet include flavonoid compounds (flavones, isoflavones, flavanones), lignans, and coumestrol from legume sprouts. While flavonoid compounds are widespread in foods of plant origin, the most significant compounds with oestrogenic activity in this class are genistein and daidzein, found in largest amounts in the soybean⁴³, and formononetin from clovers. Lignans, which are characterised chemically by a 2,3-dibenzylbutane structure are also widespread in plant foods, although the flaxseed contains concentrations which are two orders of magnitude higher than any other known source⁴⁴. Oestrogenic activity is critically dependent on the metabolism of these compounds by the microflora in the large bowel where daidzein may be either generated from formononetin or metabolised to equol ^(45,46), and the “mammalian lignans” enterolactone and enterodiol are generated from less oestrogenic precursors such as matairesinol and secoisolariciresinol⁴⁷. Descriptive studies examining urinary excretion or plasma levels of phytoestrogens in groups with different experiences of hormone dependent cancers have been summarised by Adlercreutz and Mazur⁴⁸. While phytoestrogen intakes are highest in the populations with the lowest cancer risk, this evidence remains circumstantial and experience with the correlational studies of per capita fat consumption and breast cancer should have taught us to regard this kind of evidence as encouraging, but open to many alternative interpretations. An especially exciting finding, from a case-control study conducted in Western Australia by Ingram et al, of substantially reduced risks of breast cancer associated with high urinary excretion of phytoestrogens is currently in press⁴⁹. Angiogenesis, the process by which new capillaries develop from pre-existing vessels, and on which ‘solid’ cancers are critically dependent for growth, has been shown to be sensitive to phytoestrogens especially genistein⁵⁰. Sex hormone binding globulins (SHBG) are circulating proteins which are synthesised in the liver, and which exhibit a high affinity for both oestradiol and testosterone. Since the biological activity of steroid hormones bound to SHBG is very low, their bioavailability is determined to a significant extent by the circulating levels of SHBG ⁵¹. Indeed SHBG concentrations increase in response to rising levels of either sex hormone and hence appear to be acting as regulators. The notion that phytoestrogens might stimulate synthesis of SHBG and thereby significantly reduce the bioactivity of endogenous oestrogens has been championed by Adlercreutz and coworkers⁵² but their human work was based on very heterogeneous groups of participants, and other studies, including unpublished work of our own, have failed to observe any dietary dependence of SHBG⁵³. The observation that some phytoestrogens can inhibit growth in tumours with and without oestrogenm receptors underscores the potential importance of mechanisms unrelated to phytoestrogenic activity in the prevention of malignancy. Genistein, for example, appears to be able to inhibit the tyrosine-protein kinase intimately involved in determining the activity of proteins which regulate cell proliferation⁵⁴; to inhibit topoisomerase II⁵⁵; and to arrest the cell division cycle around the G2 to M phases⁵⁶. Within the context of breast cancer, an important property of phytoestrogens may be their ability to inhibit the cytochrome P450 aromatase, which catalyses the final step in the synthesis of oestrogen and oestrone from testosterone and androstenedione respectively⁵⁷. For prostate cancer, the ability of phytoestrogens to inhibit the reductase which converts testosterone to its bioactive form in the prostate, dihydrotestosterone may be an important chemopreventive mechanism⁵⁸. Certainly this reductase has been the target of chemotherapeutic drugs such as finasteride that are currently undergoing Phase III clinical trials in the US. In many ways the phytoestrogen and cancer story is a case-study in the contemporary status of the nutritional epidemiology of cancer. Weak ecologic data shows that countries whose populations consume the largest amounts of phytoestrogen-rich foods also have the lowest incidence of hormone dependent cancers. Laboratory studies in animal models of breast and prostate cancer together with observations of the effects of phytoestrogens on cell lines either in vitro or implanted, have been encouraging, and have assisted in the identification of a considerable number of mechanisms, although the relative importance of these mechanisms individually is largely undetermined, and the ability of many phytoestrogens to act as weak agonists of endogenous oestrogens is confusing. Some of these mechanisms directly involve oestrogen signal transduction pathways, but others clearly do not. The evidence from analytical human epidemiology is both sparse and of variable quality but generally supportive of the hypothesis that phytoestrogens may be chemopreventive agents. The information is still not sufficiently convincing, either with respect to their anti-carcinogenic properties or the ‘doses’ needed to achieve them, in order to make dietary recommendations of a public health nature.

4.4. Monoterpenes

Monoterpenes such as limonene and perillylalcohol (found in the essential oils of citrus fruits, cherry, spearmint, dill and caraway and also used as flavouring agents) can inhibit the biochemical modifications required to incorporate proteins into cell membranes. Many proteins whose functionality depends on their location within membranes play important regulatory roles and it has been demonstrated that monoterpenes can prevent the incorporation into membranes of the growth signaling ras proteins which become damaged and lose control early in the carcinogenesis process.

4.5. Organosulphur compounds

Garlic and other Allium species (onions, leeks) contain organosulphides such as diallyl sulphide which can inhibit chemically induced cancers in laboratory animals. A definitive mechanism has not been established yet – but there is growing evidence that these compounds have differential effects on the Phase I enzymes (cytochrome P450 isozymes) involved in the activation/detoxification/excretion of ‘foreign’ dietary substances ^(59,60).

4.6. Dietary fibre

The term dietary fibre is a rubric for dietary components entering the large bowel having survived the digestive processes in the stomach and small intestine. Non-starch polysaccharides make up the major component of dietary fibre. People who consume diets rich in fibre typically exhibit high stool weights and low (rapid) transit times through the gut, which is the basis for hypotheses that fibre simply reduces the extent to which epithelia in the gut are exposed to carcinogens such as the secondary bile acids produced by the bacterial action on the primary bile acids required for the dispersal of dietary fats. Possibly more important, however, is the capacity of the bacterial flora in the large bowel to ferment non-starch polysaccharides. The short-chain fatty acids (SCFA) generated by fermentation include butyric acid, which, in addition to being a preferred energy substrate for colonocytes, is also capable of inducing aberrant cells to ‘differentiate’ and resume a quiescent state most closely related, in functional terms, to the mature colonocyte. Fermentation may also release sequestered minerals (like calcium) and reduce bowel pH; with both effects acting in concert to precipitate harmful bile acids. In recent years it has been increasingly appreciated that significant amounts of dietary starch may also resist digestion in the upper alimentary tract, and contribute to the fermentable substrates in the large bowel. Unripe bananas and cold cooked potatoes are rich sources of ‘resistant’ starch. Importantly, the SCFA mixture arising from the fermentation of resistant starch appears to be particularly rich in butyric acid.

4.7. Phytates (inositol phosphates)

The outer layer (bran) component of most mature nuts and seeds is rich in phytates, which are well known for their ability to sequester metals and/or minerals. It is not known whether this property is relevant to the mechanism by which phytates appear to be able to inhibit carcinogenesis initiated by the polyaromatic hydrocarbon dimethyl benzanthracene in laboratory animals⁶¹.

4.8. Indoles

Indole-3-carbinol (derived from the glucosinolate glucobrassicin in Brassica vegetables) has been intensely studied by Bradlow and associates for its apparent ability to divert oestrogen metabolism along a pathway which results in greater production of a less bioactive 2-hydroxy metabolite instead of the more problematic 16-alpha-hydroxy metabolite. This property might be protective against breast cancer.

4.9. Carotenoids

Responsible for the colouring, carotenoids are found in a variety of orange/yellow fruits and vegetables as well as some dark green leafy vegetables (spinach, cabbage and brussels sprouts). The most well known example is beta-carotene. Like many carotenoids, beta-carotene is a powerful antioxidant (a striking example being the protection it offers the algae from which it is commercially harvested against harmful ultraviolet radiation from the sun). It is also a precursor of vitamin A (retinol) and retinoic acid which have been demonstrated to have the ability to induce differentiation of neoplastic and preneoplastic cells. Intervention trials in populations at risk of skin, cervix, colon and lung cancer have failed to demonstrate any health benefits, however. The alpha-carotenoid lycopene (to which tomatoes owe their red colour) is a very powerful antioxidant which has been associated with reduced risk of prostate cancer.

4.10. Folic acid

The vitamin folic acid, from green leafy vegetables, oranges and orange juice, and the outer layers of many seeds and grains, plays an important metabolic role in the synthesis of DNA, and in situations requiring the transfer of a methyl group to a biological acceptor molecule. Methylation of DNA itself appears to be an important mechanism for controlling the expression of many genes, including those involved in cell proliferation – and abnormal methylation states of DNA (usually low methylation) have been associated with a number of neoplastic and preneoplastic conditions.

4.11. Vitamins C and E and selenium

The water-soluble antioxidant vitamin C is present in many fruits and vegetables, especially citrus and peppers.. It can prevent the formation of carcinogeniic nitrosamines from nitrite and secondary amines in the stomach. It reduces the mutagenicity of gastric juices, and plays a role in immune function. It also regenerates the intracellular fat soluble antioxidant vitamin E (a collective term for a number of tocopherols and tocotrienols). Vitamin e in turn may also keep selenium, another antioxidant. in a reduced state.

5. Role of chemopreventive agents in cancer therapy

Tumorigenesis or carcinogenesis is a multi-step process that is induced primarily by carcinogens leading to the development of cancer. Extensive research in the last few years has revealed that regular consumption of certain fruits and vegetables can reduce the risk of acquiring specific cancers. Phytochemicals derived from such fruits and vegetables, referred to as chemopreventive agents include genistein, resveratrol, diallyl sulfide, S-allyl cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins and eugenol. Because these agents have been shown to suppress cancer cell proliferation, inhibit growth factor signaling pathways, induce apoptosis, inhibit NF-kB, AP-1 and JAKSTAT activation pathways, inhibit angiogenesis, suppress the expression of anti-apoptotic proteins, inhibit cyclooxygenase-2,they may have untapped therapeutic value Tumorigenesis is a multistep process that begins with cellular transformation, progresses to hyperproliferation and culminates in the acquisition of invasive potential, angiogenic properties and establishment of metastatic lesions⁶². This process can be activated by any one of the various environmental carcinogens (such as cigarette smoke, industrial emissions, gasoline vapors), inflammatory agents (such as tumor necrosis factor [TNF] and H₂O₂), tumor promoters (such as phorbol esters and okadaic acid). This multistep process of carcinogenesis consists of three phases: tumor initiation, promotion and progression phases. Several population based studies indicate that people in South East Asian countries have a muchlower risk of acquiring colon, gastrointestinal, prostate, breast and other cancers when compared to their Western counterparts (see Table 4). It is very likely that constituents of their diet such as garlic, ginger, soy, curcumin, onion, tomatoes, cruciferous vegetables, chillies and green tea play an important role in their ability to avoid these cancers. These dietary agents are believed to suppress the transformative, hyperproliferative and inflammatory processes that initiate carcinogenesis. These inhibitory influences may ultimately suppress the final steps of carcinogenesis, namely angiogenesis and metastasis.These dietary agents have been classified as chemopreventive agents since their ability to delay the onset of the carcinogenic process has been studied extensively. Because these chemopreventive agents are derived from natural sources, they are considered pharmacologically safe. The focus of the current review, although brief, is to evaluate the untapped therapeutic potential of these chemopreventive agents in th