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Foods and Phytochemicals in Cancer Prevention

Introduction

In the past ten years scientists have been actively studying phytochemicals that have an influence on human health. From this research we have learned much about prevention and treatment of cancer. The recent Dietary Supplement Health Education Act passed in 1994 has enabled food products to make health claims if they are substantiated by scientific research. This has caused an explosion of supplements available in health food stores and the advent of the nutraceutical industry. Although many of these nutraceuticals have some evidence of preventing certain diseases, one should beware of the lack of regulation in this area.

Phytochemicals can act at almost every step of carcinogenesis, usually to improve the outcome, but sometimes as a carcinogen. These dietary components act as desmutagens in each stage of carcinogenesis by acting as carcinogen inactivators, enzymatic inducers, scavengers or antioxidants. Later in the process they may inhibit tumor growth by acting as suppressors.

Chemical Carcinogenesis

Cancer occurs when a cell loses its normal patterns of replication and begins to grow uncontrolled. The process of carcinogenesis is multistep, requiring mutations in several genes affecting cell growth. There is usually a long latency period from when the disease first begins until it is diagnosed, making treatment difficult. The process can be described by three phases: initiation, promotion and progression. Initiation is the time when the DNA of a cell is first damaged by a carcinogen and not repaired in the normal way. This step is affected by formation of DNA adducts, DNA repair, and mutation and deletions in the DNA. During promotion, the cell transforms into a premalignant phase, which is still reversible. This stage involves alterations in gene expression and cell proliferation. In the last step, progression, the mass becomes an invasive malignant mass through a variety of genetic mechanisms. This step is considered irreversible and eventually leads to metastasis.

Drug Metabolism

Exogenous agents that enter the body, including carcinogens, are metabolized by the body in an attempt to make them more soluble and thus more easily excreted. This metabolism is done by two categories of enzymes, phase I and phase II, both of which are present in high levels in the liver. Phase I enzymes include the cytochrome P-450 enzymes and generally act by exposing a polar functional group or adding a hydroxyl group. Although this reaction is aimed at making the drug more polar, it can also alter a carcinogen into a strong electrophile making it more reactive and thus a stronger carcinogen.

For instance, polycyclic aromatic amines such as benzo[a]pyrene, are considered pro-carcinogens which are converted to more active carcinogens by phase I enzymes. While many phytochemicals have been identified that inhibit these enzymes, many environmental pollutants such as tobacco smoke can induce these enzymes, thus altering the rates of drug metabolism.

Phase II reactions involve further modifications to make an agent more polar by conjugation with glucuronic acid, sulfuric acid, acetic acid or an amino acid. One example is the conjugation of glutathione to nitro groups on the drug by the enzyme GSH-S-transferase.

If a reactive foreign agent enters the nucleus of the cell it can interact with the DNA forming adducts which can interfere with replication, thus leading to mutations or deletions in the DNA. This phase of carcinogenesis is termed initiation and is reversible if DNA repair mechanisms are active. The promotion phase of carcinogenesis occurs when sufficient DNA damage has occurred to affect gene expression and cellular proliferation. This can be due to mutations in the genes that affect cell growth and signal transduction. A cell may sense abnormalities in cell growth and opt to undergo apoptosis, or cell death. At this point, apoptosis can save the entire organism by the removal of one abnormal cell. If this does not occur, tumor progression follows, which may be due to mutations in tumor suppressor genes or genes involved in apoptosis.

Oncogenic Signaling

Proteins involved in cell growth and the formation of cancer are known as oncogenes and anti- oncogenes. Oncogenes were originally defined as genes that contribute to neoplastic transformation when introduced into a normal cell. They were later found to be proteins involved in cell cycle progression. When expression of an oncogene is amplified, uncontrolled cell growth can result, leading to cancer. Anti-oncogenes, also called tumor-suppressor genes, are recessive genes responsible for slowing the uncontrolled growth, essentially the brakes of the cell cycle. If a tumor suppressor protein is missing or not functional due to mutation, then uncontrolled growth can occur.

Cell growth stimuli normally occur by the binding of a growth factor to its receptor, either on the plasma membrane or in the cell nucleus. In the case of a plasma membrane receptor, this message is then transferred to the interior of the cell and to the nucleus by signal transduction molecules. In the nucleus, transcription factors are activated that result in DNA synthesis and cell growth. Some cancers are hormone sensitive, such as breast cancer, and grow as a result of hormone binding to a nuclear receptor where it then stimulates cell growth.

One signal transduction molecule that has been associated with a multitude of cancers including colon and lung cancer, is the small G protein ras, associated with the inner face of the plasma membrane. Mutations in the ras protein result in loss of GTPase activity. Through post translational modification, 15 or 20 carbon lipid molecule (farnesyl) is added to the ras protein. This isoprenylation allows ras to associate with the plasma membrane and is essential for its activity. When activated, ras ultimately activates transcription factors such as myc and fos, thus altering gene expression. Inhibition of ras isoprenylation may result in anti-tumor activity.

Tumor suppressors differ from oncogenes in that they are recessive genes necessary for halting cell growth if mistakes in the DNA are identified. Either inherited mutations or random mutations can inactivate tumor suppressor genes leading to uncontrolled cell growth. Examples of tumor suppressors are; APC, DCC, p53 and Rb. Some of these tumor suppressor genes also play a role in apoptosis. Apoptosis is the last chance a defective cell has in limiting tumor growth before its uncontrolled growth puts the entire organism at risk. Cancer cells lose the ability to undergo apoptosis.

Carcinogenesis can be stopped or at least slowed at several stages including; alteration of phase I or phase II enzymes to decrease toxicity of the carcinogen, inhibition of DNA adduct formation, repair of mutation, alteration of signal transduction molecules that affect growth, or induction of cellular apoptosis. Much drug research centers on inhibition of signal transduction proteins, and we now know that many phytochemicals are able to affect these processes also. For instance, phytochemicals have been identified that can affect the following steps in carcinogenesis:

1. Modifying activation of carcinogens by inhibiting phase I enzymes.

2. Modify detoxification of carcinogens by activating phase II enzymes.

3. Scavenging DNA reactive agents.

4. Suppressing the proliferation of early, precancerous cells.

5. Stimulating the process of apoptosis in damaged cells.

6. Inhibiting other properties of cancer cells.

Who is at Risk for Developing Cancer?

The process of developing cancer is length and there are no established early markers as there are for heart disease, making it difficult to associate a cause. However, we know that one of the major contributors to cancer is cigarette smoke, and not just for lung cancer. Cigarette smoke can stimulate biotransformation enzymes making other carcinogens more active. There also appears to be a connection between the amount of red meat in the diet to an increased incidence of colon and prostate cancer, but that connection is unclear. Obesity and lack of exercise can also increase the risk of developing cancer. High fat diets may increase the risk of developing cancer, especially of the colon, rectum, and prostate. Many cancers also have a hereditary risk such as breast cancer and colon cancer. Any patient with a previous diagnosis of cancer is also at risk of developing a second cancer.

Foods and Herbs for Cancer Prevention

There has been an explosion of research to examine the cancer chemopreventive effects of food and food components. This is a brief survey of foods, herbs, and isolated components of them that have substantiated effects in chemoprevention in preclinical, epidemiological and some clinical settings. There is current disagreement as to whether isolated compounds extracted from food or the whole food is more important in chemoprevention. Although research is easier done on isolated components, in many cases it would appear that the whole food or herb is more potent. This may be due to a variety of active components that act additively or even synergistically and to the presence of agents that can decrease the toxicity of other phytochemicals present.

Research in the area of chemoprevention can be difficult for many reasons. First, research is done on a healthy individual and the time it takes to develop cancer in lengthy, making studies long, sometimes more than a lifetime. Finding a large enough body of compliant patients is also difficult. Researchers are looking for biomarkers that can serve as early signs of cancer. Most of the work reviews here is done in animals, and although we can never be sure exactly how that work translates to effects in humans, it is still relevant. Included below are only those foods and phytochemicals in which an overwhelming amount of preclinical, animal or epidemiological evidence exists regarding these chemopreventive effects. Hundreds of other phytochemicals are still in the earliest phases of investigation and not ready for clinical evaluation yet.

As there have recently been deaths that have occurred in patients after being injected with various herbal treatment, a word of caution must be made. These agents are meant as foods, to be taken orally by consumption, never by injection. Injections are typically not safe for many reasons.

Cruciferous Vegetables

In a review of 25 studies published in the literature prior to 1994, 20 showed a statistically significant inverse relationship between colorectal cancer and consumption of at least one vegetable group. The relationship being less striking for fruits. Vegetables contain a variety of anticarcinogens including carotenoids, ascorbates, tocopherols, selenium, folate, fiber, dithiothiones, indoles, thiocyanates, sterols, protease inhibitors and coumarins. More specifically, cruciferous vegetables such as broccoli, cauliflower and watercress, which contain high levels of indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC), have been linked to a decrease in a variety of cancers. The American Cancer Society, as well as the American Dietetic Association, recommends 5 cup servings of vegetables per day to promote good health.

I3C can induce multiple cytochrome P450 enzymes as well as phase II metabolic enzymes and can decrease the binding of carcinogen to DNA. I3C can also act as an anti-estrogen by decreasing the level of estrogen receptor and affecting estrogen metabolism (estradiol 2-hydroxylation), making it effective in the prevention of breast and prostate cancer. It has been shown to inhibit the formation of chemically induced mammary tumors in mice when given orally during either the initiation phase alone or the initiation and promotion phases. In rats, doses of 50-100 mg/day, 5x/week were non-toxic. In humans, doses of 0.7 umol/kg-bw/day were found to increase estradiol 2-hydroxylation, and doses as high as 0.04 mmol/kg-bw/day have been used. Clinical trials to investigate the role of I3C in preventing breast cancer are currently planned.

PEITC is a naturally occurring sulfur compound found in cruciferous vegetables in the form of gluconasturtin. When the plant is crushed glucosinolate releases PEITC. PEITC inhibits certain cytochrome P450 enzymes which probably accounts for its chemopreventive effects. There is evidence for its use in preventing cancer of the lung, esophagus, forestomach and hepatocellular adenomas. In toxicity studies, PEITC was shown to have adverse effects on the GI tract as well as some genotoxicity. Although a safe or effective dose has not yet been established for humans, based on animal data, an effective dose would be 0.033 umol/kg-bw/day, or 40 mg PEITC or 1.4 g of watercress. Other isothiocyanates may also be effective in chemoprevention. Phase I studies are expected to begin soon to determine safety and pharmacokinetics of PEITC using a daily dose of 10 mg and up in chronic smokers.

Garlic

Several epidemiological studies have shown that the ingestion of garlic is associated with decreased levels of various cancers. Garlic contains several sulfur compounds including S-allyl cysteine (SAC) and diallyl disulfide (DADS) which can inhibit phase I enzymes and induce phase II enzymes, thus acting as cancer preventing agents. Extracts of garlic, both odorized and deodorized reduce the transformation of precarcinogens to carcinogens by the P450 enzymes. In rats, DADS inhibits DNA damage and tumor formation, most specifically mammary tumor formation. It was found to be more potent when mixed with vitamin A and selenium. Sulfur containing compounds may also stimulate DNA repair and inhibit DNA and protein synthesis, thus making it potent in protecting against cancer. Onions and leeks are also high in these sulfur containing compounds.

Results from the Iowa Women’s Health Study showed that women who consumed more than one garlic head per week had a 32% reduction in the risk of colorectal cancer compared to those who did not eat garlic. Garlic and onions also contain antioxidant activity as well as selenium which contributes to its chemopreventive activity.

The application of oil-soluble constituents of garlic and onion (diallyl sufide and diallyl disulfide) were shown to inhibit the formation of skin papillomas on mice when administered topically.

Garlic administration has also been used as an adjuvant therapy to reduce the side effects of chemotherapy. This is probably due to its beneficial effects on the cardiovascular system.

Ginseng

A large case control study showed that patients who regularly ingested fresh ginseng extracts had a decreased risk for cancers compared with nonintakers, especially cancers of the oral cavity, esophagus, stomach, colon/rectum, liver, lung and pancreas. Recently, a study showed the effectiveness of a topical, alcohol extract of ginseng towards skin cancer in mice. Researchers applied 1-4 mg of ginseng extract per mouse prior to application of the carcinogen phorbol ester and saw a decrease in both tumor incidence and multiplicity.

Grains

Grains contain both dietary fiber and selenium, both of which contribute to chemoprevention. Dietary fiber refers to the components of plant tissue that are resistant to digestion by humans. It acts in many ways to protect against cancer: by increasing stool bulk, the contact time for carcinogens in the colon decreases; by binding with bile acids and other potential carcinogens, it reduces the concentration of free carcinogens; by lowering the fecal pH, fiber inhibits the bacterial degradation of food to potential carcinogens; and, through the production of sodium butyrate, by bacterial fermentation of dietary fiber. Sodium butyrate can induce apoptosis in colonic tumor cell lines and may be involved in inhibiting human colorectal cancer. This may explain the beneficial effect of dietary fiber in colon cancer.

Inorganic forms of selenium are converted by plants into organic selenium analogs of sulfur compounds. Since most studies on selenium use inorganic forms, and bioavailability may differ between organic and inorganic selenium, it is difficult to clearly understand the chemopreventive activity of ingesting selenium. However, low blood selenium levels are associated with a higher cancer mortality and selenium supplementation inhibits DMBA-induced mammary tumorigenesis in rats and mice. Organic selenium can be obtained through grains, vegetables and seafood, the toxicity of inorganic selenium is unknown. Selenium acts by altering carcinogen metabolism, affecting immune function, protecting against oxidant stress, and inhibiting cell proliferation.

In a recent trial to examine the role of selenium to inhibit skin cancer, patients were given 200 micrograms of selenium per day for 4.5 years. Patients were followed up for 6.4 years, and although there was not a decrease in skin cancer, there was a decrease in prostate, colorectal and lung cancers. Selenium has also been found to inhibit chemically induced and spontaneous tumor development in the mammary gland. Selenium is particularly important in the Eastern Coastal US because selenium levels in the soil and thus in the crops is very low. The high hepatoma rate in one area of China, is related to low levels of selenium in the local grain.

Monoterpenes

Monoterpenes are 10 carbon isoprenoids (5-carbon units) that are secondary products of mevalonic acid metabolism in plants. In animals the mevalonic acid pathway leads to the formation of cholesterol. These monoterpenes were first identified for their activity in controlling cholesterol biosynthesis in animals, but now over 50 monoterpenes have been found to have substantial anti-carcinogenic activity in many models. In addition to their ability to inhibit carcinogenesis, they also demonstrate the ability to induce regression of mammary, liver and pancreatic tumors in rats and have anti-tumor effects in various cell lines. Thus, they have both a chemopreventive as well as a chemo-therapeutic role. Monoterpenes are found in the essential oil fraction of many fruits, herbs and spices, as well as barley oil, rice bran oil, olive and palm oil, and wine. Lesser amounts can be found in dairy products and eggs.

Monoterpenes act at various levels to prevent and inhibit cancer growth:

1. Inhibition of protein isoprenylation, including the cell-growth associated proteins, thus inactivating .

2. Inhibition of the cholesterol pathway, which may play a role in growth inhibition.

3. Inducing apoptosis in tumor cells.

4. Inducing the expression of the liver enzymes glutathione-S-transferase and uridine diphosphoglucuronosyl transferase, thus increasing urinary excretion of carcinogen metabolites and decreasing formation of DNA adducts.

Dietary levels of isoprenoids support chemoprevention, whereas pharmacological doses are chemotherapeutic. Human studies indicate that 0.5 mmol of isoprenoids will significantly lower serum cholesterol and that 10 mmol per day provides chemoprevention.

The two most researched monoterpenes, d-limonene and perillyl alcohol are both undergoing clinical trials for the treatment of advanced stage cancers. Other important monoterpenes with anti-tumor effects are geraniol, menthol, and tocotrienol.

D-limonene is a monoterpene found primarily in the essential oil fraction from orange peel and is often used as a flavor enhancer in drinks and foods. Dietary orange peel oil (1-5%) was found to inhibit the promotion and progression of chemically initiated mammary carcinogenesis in mice and subsequently promote the regression of these tumors. Limonene has been found to decrease the incidence of many tumor types in animals including lung adenomas, skin, liver, mammary tumors and stomach tumors. Currently, limonene is under investigation as a treatment for breast cancer in humans as an alternative to tamoxifen.

A second monoterpene, perillyl alcohol, is found in the essential oil fraction of mints, lavender, and cherries. It is the hydroxylated derivative of d-limonene and is five times as potent as limonene. By selectively inhibiting isoprenylation of small guanine nucleotide-binding proteins (G proteins) by interacting with protein:prenyl transferases, perillyl alcohol can decrease the activity of the protein. The protein has a significant role in cell growth and has been identified as an oncogene in many cancers. Perillyl alcohol can also inhibit cell growth by regulating the synthesis of cholesterol and ubiquinone, as well as inducing differentiation and increasing TGF-beta receptor activated apoptosis as well as TGF-beta levels.

Perillyl alcohol has potential to inhibit colon and small intestine cancer, liver, pancreatic, mammary and prostate cancer. Currently, the NCI is carrying out phase I clinical trials for the use of perillyl alcohol for the treatment of advanced breast cancer in humans. Using a dose of 2 grams per day, there appears to be only slight renal and gastrointestinal toxicities associated with perillyl alcohol. Due to promising results, additional studies are scheduled.

Rosemary

Rosemary has recently been found to contain potent anti-cancer activity, particularly for breast cancer. Rosemary contains anti-oxidants that are more potent than the typical food additives BHT and BHA (tert-butyl-4-hydroxytoluene and tert-butyl-4-hydroxyanisol). Additionally, rosemary has anti-inflammatory activity shown by its ability to reduce the amount of nitric oxide production in mice cells. Nitric oxide released during inflammation, is a free radical that can damage DNA. Active constituents of rosemary include carnosol, carnosic acid, ursolic acid, betulinic acid, rosmaridiphenol and rosmanol, most of which are present in the essential oil fraction.

Besides acting as an anti-inflammatory and antioxidant, rosemary contributes to chemoprevention by preventing the binding of carcinogens to DNA and affecting metabolic enzymes. Researchers have found that whole rosemary extracts and its purified component, carnosol, in the diet of rats was able to prevent binding of the carcinogen, 7,12-dimethylbenz[a]anthracene, (DMBA) to DNA in breast cells. Ironically, the whole extract was more potent than the isolated component, carnosol, with another component, ursolic acid, being ineffective. Similar results were seen in the development of breast tumors in these rats with both rosemary and carnosol decreasing tumor formation by 37%, while the groups receiving ursolic acid showed little reduction in the amount of tumors formed.

Another study showed that rats fed 1% rosemary in their diet for two weeks prior to the administration of DMBA had 76% fewer DNA adducts compared to rats fed a control diet, even when excess fat was added to the diet which increases the number of DNA adducts. High fat diets are known to be associated with a higher risk for breast cancer. Significant effects were also seen with only 0.5% rosemary in the diet. Similar results have been found using human bronchial cells and liver cells. In these experiments the DNA binding of the carcinogens aflatoxin and benzo(a)pyrene were also shown to be inhibited by rosemary extract.

Besides acting by preventing binding of carcinogens to the DNA, rosemary can also affect the metabolism of some carcinogens in a way that decreases their toxicity. Enzymes found in the liver, known as P450, (GSH), and (QR) can affect the toxicity of some chemicals. Although the main role of the liver P450 enzymes is to detoxify compounds, the aromatic hydrocarbons such as DMBA are actually activated into much more potent carcinogens. Thus, DMBA, benzo[a]pyrene and aflatoxin are considered pro-carcinogens rather than direct acting carcinogens. The second group of enzymes, GSH and QR, act by detoxifying these active carcinogenic metabolites and thus protect against cancer.

When rats were fed diets containing whole rosemary extract, the phase II enzymes glutathione S-transferases and quinone reductases were increased significantly. Animals fed carnosol alone however, did not have an increase in these liver enzymes. Similar experiments using human bronchial cells and liver cells in tissue culture have shown that rosemary extract, carnosol and carnosic acid were all able to reduce the levels of P450 enzymes after treatment with benzo(a)pyrene or aflatoxin B1. In bronchial cells, rosemary extract, carnosol and carnosic acid were able to stimulate both glutathione S-transferase and quinone reductase after treatment with benzo(a)pyrene.

Although the anti-cancer properties of rosemary have been clearly demonstrated in animal studies, these have not yet led to human trials. Whole rosemary seems to be as beneficial or more beneficial than its isolated components.

Soy Products

Epidemiological studies have long shown an inverse association between the occurrence of hormone-dependent cancers (mainly breast and prostate) and the traditional soy-rich Asian diet. This anti-cancer activity has been attributed to the presence of phytoestrogens in soy. These phytoestrogens actually act as anti-estrogens by binding to the estrogen receptor and inhibiting the action of estrogen. Several types of cancer including breast cancer and prostate cancer grow in response to estrogen. Soy products have been shown to decrease a woman’s circulating estrogen levels and lengthen her menstrual cycle, lower serum 17 beta-estradiol levels, suppress FSH and LH surges and lower luteal phase prostaglandins. This results in a longer follicular phase of the cycle which is the time of lowest breast cell division, again, giving less stimulation to the breast tissue may result in a lowered risk of cancer. Vegetarian women lower their risk of getting breast cancer by 37%, possibly due to the increased ingestion of phytoestrogens. In post-menopausal women however, soy products have estrogenic effects such as increasing the cell lining of the vagina.

Phytoestrogens also have antioxidant activity. Although the most widely known source of phytoestrogens are soy products which include tofu, roasted soybeans, tempeh and soy milk and soy cheese. They also include lignans found in flaxseed, cereal bran, vegetables, legumes and fruits, and isoflavones found in soybeans, chick peas and other legumes. The flowers from red clover (Trifolium pratense) contain high levels of phytoestrogens also as well as burdock root (Arcticum lappa) which has a long folk history of use in the prevention of cancer. A bonus here is that phytoestrogens can also decrease your risk of heart disease, osteoporosis, and menopausal symptoms. Epidemiological studies indicate that as little as four ounces of tofu per day can reduce a woman’s risk of cancer, with fermented forms such as tempeh, having more bioavailability. Soy consumption has also been associated with a decrease in colorectal cancer.

The most extensively studied isoflavone in soy is genistein, a phytoestrogen found in soy beans and forage plants. Genistein has been found to inhibit breast and skin cancer in animal models. It binds to the estrogen receptor, preventing the binding of estrogen, which seems to promote breast cancer. Genistein is currently under clinical investigation by the NCI as a chemopreventive agent for breast and prostate cancer.

Tea

Both black and green tea (Camellia sinensis) contain polyphenols which have anti-cancer activity. This is partially due to polyphenols that are rapidly absorbed and spread through the body, acting as antioxidants. There are three basic types of tea: Green tea, from the fresh leaves of Camellia sinensis, contains catechins including epicatechin, epicatechingallate, epigallocatechin and epigallocatechin gallate; black tea, made by fermentation of green tea, contains theaflavins, and thearubigins; and oolong, which is partially fermented and so retains some, but not all, of the catechins.

Epidemiological evidence suggests that tea consumption protects against cancers of the breast, colon, liver, lung, pancreas, stomach and uterus in humans. The eight year Iowa study of postmenopausal women showed that those who drank two or more cups of black tea per day had a decreased risk of cancers of the digestive tract and urinary tract. Melanoma, and cancers of the pancreas, lung, breast, uterus and ovary were not affected however. There are inconsistencies between various studies, possibly due to comparing risks between different cultures which may have additional variables. Studies of lung and colon are the most inconclusive, with some studies showing an inverse relationship and others not. One study showing that heavy tea drinking (seven or more cups per day) may actually increase the risk of cancer. Animal studies and other pre-clinical experimentation, however, are convincing that green tea and probably black tea too, decrease the risks for several cancers, especially prostate and breast cancers.

A component of tea, epigallocatechin-3 gallate (EGCG), inhibits urokinase-type plasminogen activator (u-PA). This was proposed based on computer simulations, and found to be true in laboratory studies. Since higher urokinase levels are associated with tumors (especially more aggressive ones) and urokinase breaks down protein in tissue and blood, it is thought that urokinase activity contributes to the growth and metastasis of tumors. Inhibiting this enzyme may thus decrease tumor growth and metastasis. Both green and black tea extracts have been shown to inhibit both the initiation and promotion steps of carcinogenesis. The mechanisms include elevation of phase II metabolic enzymes such as glutathione-s-transferase, decrease in phase I enzymes and decrease in the formation of DNA adducts. Tea also inhibits 5 alpha-reductase, an enzyme in the estrogen pathway and thus may play a special role in hormone dependent cancers.

Another recent experiment showed that oral administration of green or black tea inhibited ultraviolet light induced cancer of the skin in mice. When the decaffeinated variety of green or black tea was administered however, the cancers were not inhibited, indicating that caffeine may be an active ingredient. Oral as well as topically applied tea was also effective.

The Chemopreventive Branch of the National Cancer Institute is proceeding with clinical studies to examine the use of tea in the prevention of stomach, lung, and skin cancer.

Turmeric

Turmeric (Curcuma longa), used extensively in curries and mustards, contains curcumin, a yellow pigment with an historical use as an anti-inflammatory and pain reliever. Some human studies have been conducted using curcumin for the treatment of inflammation, atherosclerosis and HIV. Curcumin is also an antioxidant, and found to be useful in preventing tumors of the colon, duodenum, forestomach, mammary gland, oral cavity and skin. Curcumin constitutes approximately 3% of turmeric. Rats that were given up to 2.0% curcumin in their diet for eight weeks showed no toxicity. Humans given a dose of 2,100 mg curcumin orally for 5-6 weeks showed no side effects.

Additional studies have shown that curcumin decreases chemically induced colon adenomas in rats and stimulates apoptosis as effectively as the anti-inflammatory drug sulindac which is commonly used as a chemopreventative drug for colon cancer. Doses were in the range of 2000 ppm or 0.3 mmol/kg-bw/day.

A topical administration of 0.01-2 mmol was effective against skin and oral cavity tumors in mice. Studies done with rodents have also shown that curcumin can inhibit colon, breast, and stomach cancers, at doses ranging from 0.3 to 17.4 mmol/kg-bw/day. Curcumin acts as an anti-inflammatory and an antioxidant, as well as inhibiting phase II metabolic enzymes. Curcumin may also have hormonal and antiviral effects. Because of this, the NCI is considering phase II clinical trials using curcumin, given in 50 mg doses mixed in orange juice, for dysplastic oral leukoplakia patients. Curcumin is also currently in clinical trials in AIDS patients.

There are other active ingredients to turmeric besides curcumin. A water soluble extract of turmeric, not containing curcumin, has been found to decrease forestomach tumor multiplicity and incidence in mice given benzo[a]pyrene.

Vitamins

Vitamins have been suggested by many both in the prevention and the treatment of cancer. In vitro experiments show vitamins E, A, and C having clear chemoprotective effects, but epidemiological and clinical studies are not as clear.

Vitamin A and Related Agents

Vitamin A, or retinol, plays a key role in epithelial cell differentiation, decreasing cell proliferation and stimulating angiogenesis. Because deficiencies in vitamin A have been associated with an increased risk of cancer, it has received much attention in chemoprevention. Retinoic acid is effective at inhibiting rat mammary tumorigenesis and optimizing the efficacy of tamoxifen as a chemopreventive agent. Clinical trials are ongoing to determine the role of retinoic acid as a chemopreventive agent for breast cancer, head and neck cancer and prostate cancer, but there is also evidence that it reduces the risk of bladder cancer. The maximum tolerated dose for humans of 9-cis-RA is 100-140 mg/m2. Natural analogues of retinoids have been found to be less toxic than synthetic retinoids. Care should be taken for the pregnant patient however, since large amounts of retinoids can be teratogenic.

Some carotenoids can be converted into vitamin A and are abundant in green leafy vegetables, orange vegetables, dandelion leaves and stinging nettle. Beta-carotene may inhibit cancer by acting as an antioxidant, by modulating the immune system and by modifying enzymatic activation of carcinogens. In a study examining the protective effects of vitamins E, C, and A, high intake of carotinoids in the form of fruits and vegetables was shown to reduce the risk of lung cancer. Several studies suggest that the ingestion of a variety of retinoids and carotenoids are more beneficial than vitamin A alone in preventing cancer. Lycopene, found in tomatoes, ruby red grapefruit and red peppers has been shown to protect against prostate and cervical cancer.

Vitamin C

Vitamin C or ascorbic acid, is a powerful, water soluble, and non-toxic antioxidant. Its presence in fruits and vegetables, may account for some of the beneficial effects of these foods. Epidemiological studies support the benefits of vitamin C in the prevention of cancer, while animal studies do not. Ascorbate can block the formation of carcinogens such as nitrosamines. In a 19 year study examining lung cancer incidence (First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study) which examined 3,968 men and 6,100 women, vitamins C, E, and carotinoid intake were associated with a reduced risk of lung cancer in smokers and non-smokers. Smoking, of course, attenuated the protective effect somewhat.

Vitamin E

Tocopherols (vitamin E) occur in polyunsaturated vegetable oils and in the germ of cereal seeds (wheat germ) and palm oil. Again, vitamin E acts as an antioxidant as well as a blocker of nitrosamine formation. The literature regarding vitamin E is also inconsistent and not convincing for its use in chemoprevention.

Vitamin D

Vitamin D (alpha-(OH)D3) – has been shown to inhibit rat mammary tumors. Due to the potential imbalance that vitamin D may cause in calcium metabolism however, further studies need to be done to establish the role for vitamin D in chemoprevention.

Folate or folic acid

This water soluble B vitamin complex cannot be synthesized by mammals and must be supplied in the diet by liver, leafy green vegetables, legumes and cereals. Folate is necessary for methylation reactions and synthesis of DNA nucleotides. DNA methylation is involved in gene regulation and is necessary for inhibiting gene transcription. Hypomethylation of genes has been identified in colorectal cancers and an inverse association with folate is observed in this cancer. Overall, the effects of folic acid on carcinogenesis are complex and not fully understood, however, the NCI is proceeding with clinical development of folic acid as a chemopreventive agent.

Wine

Wine contains resveratrol, also common in mulberries and peanuts. This compound shows early evidence of inhibiting initiation, promotion and progression of cancer in vitro experiments. In mice studies, resveratrol was able to inhibit chemically induced skin tumors when applied to the skin at doses of 1-25 umol. Wine grapes also contain ellagic acid, which is an antioxidant and has been found to decrease the rate of esophageal tumors in rats. Ellagic acid is also found in berries and nuts.

Other

Omega-3-fatty acids – may reduce cancer risk, especially for breast and gastrointestinal cancers. Its inhibitory action on cancer is related to its ability to inhibit prostaglandin synthesis. The best source of omega-3-fatty acids is fish oil but plants high in this oil include borage and flax seed.

Antioxidants – antioxidants scavenge active oxygen species such as hydroxyl radical, superoxide anion, and singlet oxygen. They can also interfere with lipid peroxidation, xanthine oxidase activity and nitrite/nitrogen oxide production. Oxidant stress has been linked to both the initiation and post-initiation stages of carcinogenesis, thus antioxidants are often found to be chemopreventive. Most herbs (see rosemary) are found to contain potent antioxidants.

Antioxidants may also have an effect on phase I and/or phase II biotransformation enzymes and can affect carcinogen metabolism. These antioxidants include phenols, alcohols, and lactones.

Anti-inflammatories – anti-inflammatory agents can decrease arachidonic acid release and metabolism by diminishing activity of phospholipases A2 and Cgamma1, cyclooxygenase and lipoxygenase. Prostaglandin biosynthesis has been linked to both the initiation and postinitiation stages of carcinogenesis. Thus, anti-inflammatories are often found to be chemopreventive agents as is evidenced by the recent advice for those at risk of colon cancer to take an aspirin each day and by the development of new non-steroidal anti-inflammatory agents (e.g., Sulindac) for the prevention of colon cancer. Many herbs (see rosemary) are found to contain potent anti-inflammatories.

Complementary Herbs to Chemotherapy

Most patients after being diagnosed with cancer, opt to undergo chemotherapy, which can have devastating side effects. This is an area where herbs can be used both to counteract some of the side effects as well as increase the efficacy of the chemotherapy. Although rigorous clinical trials have not been performed on these agents, they have a long history or efficacy and low toxicity. This is a list of some herbs that may provide relief.

Gastrointestinal tract problems and emesis

Although many improvements have been made to control emesis associated with chemotherapy, it remains a problem that most patients fear. Native Americans used Holly, (Ilex vomitoria) and Spurge (Euphorbiae) to control emesis. In addition, Catnip (Nepeta cataria), Chamomile (Matricaria chamomilla), Ginger (Zingiber officinalis), and Red Raspberry (Rubus spp.) can help comfort nausea caused by chemotherapy. Care should be taken with ginger however as it can also inhibit blood clotting. If a patient is already losing blood clotting ability due to chemotherapy, ginger can worsen that.

Stimulating the immune system

Maintaining a strong immune system is important, both to minimize the cancer and to counteract the suppressive effects chemotherapy has on the immune system. Two important immune stimulants are Echinacea (Echinacea purpurea or pallida) and Astragalus (Astragalus membranaceus). Many studies have shown the positive effects of Echinacea on the immune system and its ability to enhance the function of mononuclear white blood cells. The root, upper parts or whole plant, expressed as a juice or as an alcohol extract are all effective. Astragalus has also been documented to improve the immune system and its use might also reduce the risk of getting cancer or having a recurrence of cancer. These herbs can also be taken prior to surgery to reduce the risk of infection.

Stimulating blood components

Dose limiting effects of chemotherapy include reduction of platelet and red blood cell number. Although very few scientific studies have been interested in these aspects, there is some evidence that Agrimony (Agrimonia pilosa) can stimulate blood clotting, and Angelica (Angelica archangelica) can activate the spleen and tone the blood. Nettle infusion may also promote blood clotting.

Liver protection

As a powerful toxin itself, chemotherapy can damage the liver. Using a tincture of Milk Thistle (Carduus marianum) or an extract of its active ingredient silymarin prior to chemotherapy may help liver function and possibly increase efficacy of the cancer therapy.

Listlessness

Cancer patients often find themselves weakened by both the cancer itself and its treatment. An extract of Ginseng can help restore energy. In fact, in Russia, Siberian Ginseng (Eleutherococcus senticosus) is sometimes given along with chemotherapy. To decrease restlessness that may lead to a lack of sleep, skullcap (Scutellaria lateriflora) and valerian (Valerian officinalis) can help.

There is ongoing research to find drugs that can improve the effectiveness of chemotherapy, allowing a lower dose to be used and improving the quality of life in patients. Some of these agents are from herbs, such as curcumin, and compounds from Nigella. Mistletoe extracts such as Iscador or Eurixor, which are used by injection, have been shown to enhance the immune system of breast cancer patients, and may even have a negative effect on the cancer itself. Hopefully, there will be advances made in this area soon.

Patient Recommendations

For patients interested in how to decrease their risk of developing cancer by using foods, the following is general advice:

1. Eat a wide variety of foods, fruits, vegetables, legumes and whole grains.

2. Eat 5 servings of fruit and vegetables per day.

3. Season your food with a variety of herbs, and drink herb teas, especially herbs high in antioxidants.

4. Avoid obesity.

For patients concerned about the development of specific cancers, the following lists agents with chemoprotective ability towards specific cancers.

Breast Cancer – Patients concerned about the development of breast cancer should be advised to increase their consumption of cruciferous vegetables, and garlic and possibly supplementing with indole-3-carbonol. Because of the promising results of monoterpenes such as perillyl alcohol, perhaps patients could be referred to cookbooks that use essential oils.

Lung Cancer – Patients concerned about the development of lung cancer should first off, quit smoking. Increasing the consumption of cruciferous vegetables is important for the isothiocyanates they contain. Selenium, which can be found in grains and seafood has also demonstrated chemoprotective ability in lung cancer.

Prostate Cancer – Oftentimes prostate cancer is hormone dependent and thus the consumption of additional soy products can decrease the risk of prostate cancer. Both selenium and tea have been shown to provide chemoprotection for prostate cancer.

Gastrointestinal Cancer – The most important factor in decreasing the risk of gastrointestinal cancer, specifically colorectal cancer is to decrease the consumption of fat and increase the consumption of fiber. Selenium may also provide some protection as well as herbs high in antioxidants. The increased consumption of fruit and vegetables is also inversely related to the incidence of rectal cancer.

Skin Cancer – Skin cancer is one of the most rapidly increasing cancers in terms of incidence. Some herbs taken internally have been shown to provide protection from skin cancer such as tea, and silymarin from milk thistle. These compounds may also provide protection when used topically along with a sunscreen.

Stomach Cancer – Increased acidity in the stomach by ingestion of vitamin C can decrease the incidence of stomach cancer. Increased fruit and lettuce associated with a lowered risk of stomach cancer, as well as garlic consumption.

Head and Neck Cancer – Increasing the consumption of fruit and vitamin A is associated with decreased risk of head and neck cancer.


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