The Intelligent guide to good health and longevity through optimal nutrition

Summary

Consuming green tea may help to prevent certain cancers as well as cardiovascular disease. Green Tea contains a class of polyphenols called catechins, most notably, EGCG which has been shown to prevent or slow cancer growth in laboratory experiments and animal studies. Human epidemiological (population) studies have shown mixed results, but are largely encouraging. Green tea consumption may also help to prevent cardiovascular disease through various mechanisms such as exerting a favourable effect on serum cholesterol levels. Large-dose green tea extract supplements may be harmful and may not be as beneficial as drinking green tea several times a day. Green tea does contain caffeine, but not as much as black tea or coffee.

Headings and Subheadings

• Green Tea, Black Tea & Oolong Tea
• Tea Polyphenols: Catechins
• Cancer: In vitro
• Cancer Fighting Mechanisms:
  • Antioxidant Activity
  • Inducing Apoptosis
  • Cell Cycle Arrest
  • Inhibition of Angiogenesis
  • Stabilization of p53 Tumour Suppression Gene
  • Inhibition of uPA Activity
  • Other Mechanisms
• Specific Cancers
• Breast Cancer
  • Animal Studies
  • Human Studies
• Gastric Cancer
  • In vitro
  • Animal Studies
  • Human Studies
• Lung Cancer
  • In vitro
  • Animal Studies
  • Human Studies
• Prostate Cancer
  • In vitro
  • Animal Studies
  • Human Studies
• Esopageal Cancer
  • Animal Studies
  • Human Studies
• Skin Cancer
  • In vitro
  • Animal Studies
  • Human Studies
• References

 

Green Tea, Black Tea & Oolong Tea

The three types of tea (black, green and oolong) are all made from leaves of the same plant (Camellia senesis) however undergo different processing which alters their flavour and chemical composition. Most tea consumed is black tea, which represents approx 78 % of the tea produced and consumed, primarily in Western countries and some Asian countries. [1] Producing black tea involves allowing the leaves to wither or dry, losing most of their moisture content which reduces their weight by approximately 50%. The dried leaves are rolled and crushed, which initiates fermentation. This fermentation initiates enzymatic reactions designed to alter the flavour (which gives black tea its distinctive taste) but in the process, causes oxidation reactions to occur which results in a significant loss of catechins. [2] Oolong tea represents only about 2% and is consumed in south-eastern China and Taiwan. Oolong tea is made by using a similar process, however is only about half as fermented as black tea. [3,4]

Green tea represents about 22% of the tea consumed, primarily in China, Japan, India, and in a few countries in North Africa and the Middle East. Green tea is made from freshly harvested leaves that are rapidly steamed or pan-fried, which inactivates certain enzymes and prevents fermentation, thus retaining most of its catechin content. [4,5]

Tea Polyphenols: Catechins

Green tea contains a variety of polyphenols, in fact the polyphenolic content represents about 30% of the dry weight of green tea.[4] The most important class of polyphenols found in green tea thought to be responsible for its anti-cancer benefits are known as catechins. The major catechins found in green tea are called epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG). Of these four catechins, EGCG is the most abundant and has shown to be the most important cancer inhibiting chemical found in green tea. [5- 8]

Studies examining the anti-cancer effects of green tea have used green tea itself, green tea extract (GTE), the polyphenol content alone (green tea polyphenols: GTP), the catechin content alone (green tea catechins: GTC) or individual catechins, most notably EGCG.

The primary catechins found in black tea include theaflavins (accounting for approx 4% of dry weight) and thearubigins (accounting for approx 20% of dry weight), which come about during the fermentation of tea leaves. These theaflavins and thearubigins are the chemicals that give black and oolong tea their characteristic colour and flavour. [4,8] One cup of green tea has about 375 mg of catechins. (Atukorale, 2002). Tea is usually steeped in hot water (approx 100g tea leaf per 100ml of water) for 3 to 5 min. A typical serving of tea contains about 250 to 350 mg tea solids. Steeping tea for 5 minutes releases approx 85% of its antioxidants whilst steeping for additional 5 minutes releases a further 15%. [5] Because longer steeping/brewing times releases more solid content into the water, the tea will taste increasingly strong/bitter with increasing steeping, however 10 minutes in hot water would be best to release the maximum antioxidant content.

Adding milk to tea does appear to decrease its antioxidant / anti-mutagenic potential, however it does tend to decrease its catechin content.[9] Because green tea’s anti-cancer potential comes from more than just its antioxidant / anti-mutagenic properties, it is probably best to consume it without milk. Moreover, holding tea in the mouth for approx 30 seconds before swallowing will significantly increase salivary concentrations of catechins, and therefore be more likely to protect against cancers of the mouth and esophagus as well as protecting against dental carries due to its anti-bacterial action. [10]

Tea contains caffeine, usually representing 3 to 6 percent of the dry weight of brewed tea. Although decaffeinated green tea is available, it has even less catechin content than black tea. [3]

Cancer: In vitro

Much of the research examining the cancer fighting properties of chemicals such as green tea polyphenols have been conducted in laboratory test tube experiments called “in vitro” studies. In vitro literally means “in glass” and refers to experiments examining the effects of live cells and tissues in a test tube or Petri dish, as apposed to “in vivo” which refers to experiments looking at the effects inside actual living organism, whether it be animals or humans.

In vitro studies using human cancer cells have shown that Green tea polyphenols can inhibit tumour growth in cancers of the oral cavity [11] Breast [12] , Lung [13,14] , Colon [15,16] Skin [17] Leukemia [18] Pancreas [19] Liver [20] and Prostate. [21] It should however be noted that many of these studies have used concentrations of polyphenols higher than what is likely to be found in human plasma after tea consumption.

Cancer Fighting Mechanisms

There are several mechanisms and combinations of mechanisms by which green tea polyphenols are known to fight cancer, however there may be more which have not yet been identified. Some of the common mechanisms well investigated are discussed below:

Antioxidant Activity : Antioxidants help to defend against free radicals, (highly reactive and destructive chemicals containing unpaired valence electrons) which can cause damage to cell membranes and DNA that can lead to carcinogenesis (cancer formation) as well as heart disease. Green tea polyphenols, particularly the catechins EGCG and EGC, are extremely powerful antioxidants. In fact, green tea catechins have shown greater free radical scavenging abilities and stronger protection against mutagenic effects (using the Ames test) , DNA scissions as well as enzymatic and non-enzymatic oxidation, than any of the other known powerful antioxidants including resveratrol, selenium, curcumin, vitamins C and E, quercetin dihydrate, sulforaphane, ellagic acid dihydrate, glutathione reduced, trolox, butylated hydroxanisole (BHA), butylated hydroxytoluene (BHT), and N-acetyl-L-cysteine (NAC).[22]

Using the Oxygen Radical Absorbance Capacity (ORAC) method to investigate the antioxidant activity of various foods found that green and black tea both have a much higher antioxidant activity against peroxyl radicals than garlic, kale, spinach, Brussels sprouts, and all the other vegetables known to have the highest antioxidant properties according to ORAC values. [23] Using the Tocol Equivalent Antioxidant Capacity (TEAC) method found that epicatechin and catechins are among the most potent of 24 plant-derived polyphenolic flavonoids. [24]

Whilst green tea catechins have shown powerful antioxidant properties in laboratory test tube studies, these studies do not take into account their bioavailability and/or metabolism [3]), however human clinical studies have found that within 30 to 60 minutes of consumption of a single dose of tea, the plasma (liquid portion of blood) antioxidant capacity of healthy adults was improved. [25-28] Human clinical trials have shown that although smokers have higher levels of oxidative damage from free radicals in cigarette smoke, when given green tea, smokers had significantly less oxidative damage.[29]

Whilst green tea possesses powerful antioxidants itself, its consumption can also increase the activities of antioxidant and detoxifying enzymes within the body, such as glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, and quinone reductase.[30]

Because many people may be unfamiliar with the complex pathology of cancer development and growth, the protective abilities of antioxidants have become a very overestimated by the public due to exaggeration by the mass media. Although antioxidants can defend against free radicals, (which may cause cancer) there is a great deal more involved in the pathogenesis of cancer than free radicals alone; consequently antioxidants may have very limited potential to defend against tumour development and growth. Discussed below are some of the other mechanisms which green tea polyphenols possess which have been shown to protect against carcinogenesis (cancer development).

Inducing apoptosis : Apoptosis is a normal programmed cell death that occurs in all normal cells so that old cells can be replaced by new ones. In cancer cells, apoptosis fails to occur, so the new cells continue to grow, but the old cells remain also. As a consequence, a large uncontrolled growth (tumour) begins to spread. Many chemotherapy drugs are designed to induce apoptosis among cancer cells to slow tumour growth and progression. One of the major mechanisms by which green tea polyphenols have been shown to be able to inhibit cancer growth in a wide variety of human and animal tumours is by causing apoptosis to occur in cancer cells whilst not affecting normal healthy cells.[31-36]

Cell Cycle Arrest: All cells undergo reproductive stages known as the cell cycle. Through a variety of complex biochemically mediated pathways, green tea polyphenols have been shown to be able to arrest (stop) the cell cycle of rapidly dividing cancer cells and thus inhibit the progression of tumour growth whilst not affecting normal healthy cells.[37] They have also shown to be able to modulate cellular proliferation by inhibiting signal transduction pathways leading to the activation of important transcription factors activator protein 1 (AP-1) and nuclear factor B (NF-B). [38-41]

Inhibition of nitrosation reactions: Chemicals called nitrites can react with amino compounds to form a type of chemical called N-nitrosamines which are known carcinogens (chemicals which cause cancer). Green tea polyphenols have been shown to inhibit these reactions. [42,43]

Inhibition of Angiogenesis: Tumours have an extremely high energy and nutrient requirement. So that tumours can grow and spread, they cause new blood vessels to grow in the area to provide the cancer cells with adequate nutrients. In fact, when radioactive dye is pumped through the blood supply and looked at on an x-ray (angiogram), the thick tumour mass with its large blood vessel supply tends to look like a crab (the tumour resembling the body, the blood vessels resembling the legs) which is where the term “cancer” comes from (cancer is Latin for crab). This growth of new blood vessels to the area is known as angiogenesis. The greater the angiogenesis, the more blood supply reaches the tumour, which means it can grow and spread (metastasize) rapidly. Consequently, one method of treating cancer is attempting to inhibit this growth of blood vessels. Many studies have shown green tea polyphenols have the ability to inhibit angiogenesis, thus slowing tumour growth and metastases. [44] It is suggested that green tea polyphenols stop angiogenesis by inhibiting vascular endothelial growth factor receptor phosphorylation. [45]

Stabilization of p53 Tumour Suppression Gene : The p53 protein is a transcription factor that regulates the expression of a wide variety of genes involved in cell cycle arrest, apoptosis, DNA repair and cellular differentiation (all factors involved in cancer growth) in response to genotoxic or cellular stress. P53 was discovered about 20 years ago however it was not recognized as a tumour suppressor gene until 10 years after its discovery. It is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Studies have shown that green tea polyphenols have been able to stabilize expression of the p53 tumour suppressor gene, thus enable cell cycle arrest, apoptosis, DNA repair and normal cellular differentiation; all characteristics lacking in cancer cells. [46-49]

Inhibition of uPA activity: Human cancers need proteolytic enzymes to invade cells and form metastases. One of the most frequently over-expressed proteolytic enzymes in human cancers is called urokinase (uPA). Inhibition of uPA can decrease tumour size or even cause complete remission of cancers in mice.[50,51]

The known uPA inhibitors are unlikely to be used in anticancer therapy because of their weak inhibitory activity at low doses and strong toxicity at high doses. The green tea catechin EGCG binds to uPA interfering with the ability of uPA to recognize its substrates and inhibit enzyme activity. [52]

Although EGCG is a weaker inhibitor than a well known anti-cancer drug used to inhibit uPA activity called amiloride amiloride, EGCG can be consumed in much higher doses without any toxicological effects. Amiloride is administered in a maximum dose of 20 mg per day, whereas a single cup of tea contains 150 mg EGCG. [53] Therefore it has been suggested that among the many mechanisms by which green tea polyphenols such as catechins manifest anticancer activity is due to the inhibition of uPA activity. [54]

Other Mechanisms : There are many other mechanisms by which green tea polyphenols have shown to inhibit carcinogenesis and tumour growth, including inhibition of other enzymes related to tumour promotion such as cyclooxygenase and lipoxygenase[55],inhibition of activator protein-1 [56], inducing Nonsteroidal Anti-inflammatory drug activated Gene (NAG-1) expression, [57]inhibition of the cancer-associated enzyme telomerase , [58]modulation of carcinogen-metabolizing enzymes and trapping of ultimate carcinogens [59-61]and reducing the production of prostaglandin E2 (PGE2). [62]

Specific Cancers

Both animal experiments as well as human population (epidemiological) studies looking at the relationship between tea consumption and cancer are discussed below. It should be noted that because green tea consumption is very rare in Western countries, most of the epidemiological studies which have assessed cancer risk in relation to green tea intake have been among Asian populations where green tea is commonly consumed. Epidemiological studies assessing cancer risk in relation to tea intake in western populations have mostly looked at black tea.

Breast Cancer

Animal Studies

• 1995: University of Chicago: ECGC injected into nude mice (mice without the ability to produce T cells, specifically bread so that they can not reject tumours or transplants on their own) rapidly inhibited the growth of tumours formed by human breast cancer. [63] Conclusion: “It is possible that there is a relationship between the high consumption of green tea and the low incidence of prostate and breast cancers in some Asian countries.”

• 1997: Nagoya City University Medical School. Researchers conducted two separate controlled experiments on rats, both using the chemical carcinogen DMBA, which takes between 50 – 140 days to cause mammary (breast) tumour growth to appear. The first group of rats were exposed to DMBA after 1 week of being fed catechins. They were fed catechins for another 1 week, and then an ordinary diet for 35 weeks. There were no difference in tumour growth between the rats fed catehins and controls. The second experiment exposed the rats on an ordinary diet to DMBA, and then a week later, started them on a catechin diet for the next 35 weeks. In this group, there was a significant decrease in mammary tumour in the rats given catechins for 35 weeks than in controls. Two speculations could be made from these results. Perhaps green tea catechin consumption during exposure to a carcinogen may not inhibit cancer growth, whereas consumption after exposure may. Or, perhaps it these results mean that short term consumption of green tea catechins may not inhibit breast cancer but long term consumption does. Due to the unusual methodology of this study, further experiments like this were needed.[64]

• 1997: Nagoya City University: once again, rats were exposed to the chemical carcinogen DMBA used to induce mammary cancer. They were then given either a diet containing ECGC or an ordinary diet. No difference in tumour growth was seen between the two groups. Conclusion: “These results indicate that green tea catechins are not effective at inhibiting progression of rat mammary carcinogenesis” [65]

• 2001: Boston University School of Medicine: Again, rats were exposed to the chemical carcinogen DMBA, only this time; all rats were given the same solid diet, but were classified by whether they were given either pure water or water containing green tea to drink. The rats given green tea showed a significantly longer latency period in tumour growth (it took a longer time before they developed cancer) as well as a significant decrease in mean tumour burden (a measure of the degree of disease involvement) by comparison with those given water (controls). In this study, the rats were not given ECGC in their food, but were given green tea in their drinking water. Because humans drink green tea rather than eat ECGC, this study was better designed than the previous ones. Conclusion: “..green tea had significant chemo-preventive effects on carcinogen-induced mammary tumorigenesis in female S-D rats.” [66]

• 2001: University of California: Green tea extract (GTE) significantly suppressed the size and decreased the tumour vessel density of breast cancer cells transplanted into mice. Conclusion: “Our data showed that mixed GTE and its individual catechin components were effective in inhibiting breast cancer and endothelial cell proliferation.” [67]

• 2002: Kurume University: In a 20 week long experiment, rats implanted with breast cancer cells (RIII/MG ) were given either 0.1% or 1.0% catechin (containing approx 50% ECGC) or no catechins at all. The rats given no catechins formed a tumour after 13 weeks and the tumour formation rate in the 20th week was 40%. A tumour began to grown by the 13 th week in the rats given 0.1% catechins as well, however the tumour formation rate in the 20th week was only 20%. The rats given 1.0% catechins grew no tumour at all, even by the end of the 20 weeks. [68]

• 2004: Harvard Medical School: Female mice implanted with human breast tumours were fed several different diets. Feeding green tea to mice reduced the size of tumours by 56% and by 72% when fed green tea plus soy phytochemical concentrate. Conclusion: “Our study suggests that dietary soy phytochemical concentrate plus green tea may be used as a potential effective dietary regimen for inhibiting progression of estrogen-dependent breast cancer.” [69]

Human Studies

Most of the studies which have looked at breast cancer risk and tea consumption have found no association, however these studies have mostly looked at black tea consumption.[70-80] There have not been many human studies to look specifically at green tea consumption in relation to breast cancer, but those that have been conducted thus far show encouraging results. In 1998, researchers at the Saitama Cancer Centre Research Institute’s Department of Epidemiology examined the association between consumption of green tea prior to the onset of breast cancer and various clinical parameters assessed at surgery among 472 breast cancer patients. [81] Two of the most important clinical factors known to determine the prognosis of breast cancer outcomes are axillary lymph node metastases (breast tumours that have spread to the lymph nodes) and expression of progesterone receptor (PgR) and estrogen receptor (ER) [82] The results of this study found that increased consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal patients with stage I and II breast cancer and with increased expression of progesterone receptor (PgR) and estrogen receptor (ER) among postmenopausal ones. A 7 –year follow up study of these patients found that increased consumption of green tea was correlated with decreased recurrence of stage I and II breast cancer. Only 24% of patients consuming 4 or less cups per day had a reoccurrence, and only 17% of those consuming 5 or more cups per day had a reoccurrence. The authors concluded:

“Our results indicate that increased consumption of green tea prior to clinical cancer onset is significantly associated with improved prognosis of stage I and II breast cancer, and this association may be related to a modifying effect of green tea on the clinical characteristics of the cancer.”

After the results of this study were published, a different research team set out to see whether the same inverse association between green tea consumption before breast cancer diagnosis and the risk of reoccurrence could be seen among a different group of patients.[83] The Hospital-based Epidemiologic Research Program at Aichi Cancer Centre was started in 1988, in which information on lifestyle was routinely collected from all first-visit outpatients by questionnaire. A total of 1160 women who were diagnosed with breast cancer between 1990 and 1998 were followed up through December 1999. During this time, 133 women (12%) suffered a recurrence of breast cancer. From the information obtained through initial patient surveys, the risk of recurrence was assessed with reference to daily green tea consumption. The results of this study showed that women with stage I breast cancer that consumed 3 or more cups per day prior to their initial diagnosis had a 57% reduced risk of reoccurrence, whilst those who consumed between 3 and 5 cups per day had a 63% reduced risk of reoccurrence. Green tea drinking women with stage II breast cancer also had a reduced risk, however not as significant (3 cups/day = 29%). The authors concluded:

“…our results provide an epidemiologic pointer suggesting that regular green tea consumption has the potential not only to prevent cancer formation but also growth, invasion and metastasis in the progression phase.”

These studies suggest that green tea consumption may favourably affect the prognosis of breast cancer outcomes, however only two major studies have looked at whether green tea consumption may prevent breast cancer occurring at all. The results of these two studies contradict each other.

The first, a case control study, was published in 2003 in the International Journal of Cancer. Between 1996 and 1998, Dr Anna H. Wu, Professor of Preventative Medicine and her colleagues at the University of Southern California’s Medical School, compared various factors between 501 breast cancer patients with 594 controls.[84] Both cancer patients and women without cancer were women of Asian descent who were living in Los Angeles. They collected information on menstrual and reproductive factors, lifestyle factors such as smoking, alcohol consumption, physical activity etc, age at menarche, parity, menopausal status, use of menopausal hormones, body size, family history of breast cancer and dietary habits including intake of soy, dark green vegetables, coffee, black tea, herbal tea and green tea. The results showed that more than any other factor, compared to women who did not drink green tea regularly, there was a significant trend of decreasing risk with increasing amount of green tea intake; in fact, the significant inverse association between risk of breast cancer and green tea intake remained after further adjustment for other potential confounders. They found that consuming approx 85ml (1 cup) per day of green tea reduced the risk of breast cancer by approx 30%, and consuming more than 1 cup/day reduced the risk by approx 50%. There was a slight decrease in risk associated with soy consumption, but other than that, no other factors appeared to be as significantly different between cases (women with breast cancer) and controls (women without breast cancer).

The second study was published in the British Journal of Cancer in 2004 by Dr Yoshitaka Tsubono, Professor of Clinical Epidemiology at Tohoku University’s Graduate School of Medicine. [85] Prof Tsubono and colleagues assessed green tea consumption among two cohort groups totalling 35 000 women over 40 years old residing in rural Northern Japan. Two hundred and twenty two cases of breast cancer were diagnosed throughout this time. No association between consumption of green tea and the risk of breast cancer was found at all. It could be argued that the results of the case control study by Prof Wu would be a better indicator because there were over 500 cases of breast cancer with which to compare, whereas the second cohort study by Prof Tsubono assessed only 222 cases of breast cancer. Either way, because of these conflicting results, further human studies are needed before a definite link between green tea and breast cancer can be ascertained. Another cohort study in Japan failed to show that drinking green tea prevented breast cancer, however the cohort was made up of women who were survivors of the Hiroshima and Nagasaki atomic bomb. [86]

Evidently those who have lived through an atomic bomb blast may not have much chance of preventing breast cancer. Because most people will probably never be subjected to such extreme circumstances, the results of this study can hardly be extrapolated to the rest of the population. Personally, I’d be happy enough just to be still alive after an atomic bomb hit my neighbourhood.

Gastric Cancer  

In Vitro  

In vitro, green tea has shown to be able to significantly inhibit the growth of human gastric tumour cells.[87]  

Animal Studies  

• 1992: Rutgers University: Female mice were given N-nitrosodiethylamine (NDEA), (a nitrosamine carcinogen used to induce lung and stomach cancer) once a week for 8 weeks and were killed 16 weeks after the last dose. Even though the heavy carcinogen exposure caused 90% of the mice to grow tumours, mice given 1.25% green tea infusion as their drinking source had 26% less stomach cancer than controls, and a reduced tumour multiplicity (the actual numbers of tumours in each mouse) by 63% by comparison with mice given no green tea at all. [87]

• 1993: University Hospitals of Cleveland: Green Tea polyphenols added to drinking water of mice consumed 30 minutes prior to carcinogen exposure. Rats fed the green tea had 71% less stomach cancers than those not fed green tea (controls). [88]

• 1993: University Hospitals of Cleveland: Mice fed water extract of green tea had 80% less stomach cancers than those which were not given green tea. [89]

• 1995: Kyoto Prefectural University of Medicine: Rats who were exposed to N-methyl-N'-nitro-N-nitrosoguanidine were either given ECGC or not. Those treated with ECGC had 50% less stomach cancer than those which were not. [90]

• 1996: Kyoto Prefectural University of Medicine: Green Tea Extract (GTE) and EGCG inhibited N-ethyl-N'-nitro-N-nitroguanidine (ENNG)-induced duodenal carcinogenesis in the mouse (cancer formation in the small intestine), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis of the glandular stomach in the rat (cancer formation of the stomach), and azoxymethane-induced colon carcinogenesis in rats. [91] The authors concluded: “These findings suggest that EGCG and GTE are useful in preventing gastrointestinal carcinogenesis, and the clinical usefulness of GTE, which has no harmful effects and is inexpensive, should be studied further.”

Human Studies  

In 1993, researchers at the Chinese Cancer Research Foundation Association examined the effect of green tea extract to the formation of carcinogenic compounds containing the nitroso- group, such as N-nitroso-proline in 135 patients at high risk of stomach cancer; 45 had superficial chronic gastritis, 45 had intestinal metaplasia, and the other 45 had atypical hyperplasia (irregular overgrowth of cells). The patients were examined with a gastroscope and classified pathologically, revealing that green tea extract blocked N-nitroso-proline synthesis, with blockage rate of 91% in superficial chronic gastritis, 94% in intestinal metaplasia and 93% in atypical hyperplasia and gastric cancer. [92] The authors concluded:

“These results will be of great significance in preventing gastrointestinal cancer.”

A case control study published in 1998 which examined differences in diet and lifestyle factors between 272 gastric cancer patients and 544 age matched controls in China found that fresh vegetables and fruits as well as green tea significantly decreased the risk of gastric cancer, whilst Over consumption of fish sauce, pickled food, mouldy cereals, irregularly taking meals and familial history of malignancy significantly increased the risk. [93]

Between October 1991 and December 1993, researchers from Shanghai Medical University conducted a population-based case-control study of stomach cancer among residents of Shanghai that were under 80 years. Information was collected on 711 people with gastric cancer and compared to 711 people without, who were of the same age and lived in the same area. The results showed 30% less gastric cancer among green tea drinkers compared to non drinkers; in fact the risk decreased even more among those that consumed the most green tea. Moreover, among drinkers of green tea, the risk of stomach cancer did not depend on the age when habitual green-tea drinking started. To date, this study has investigated more cases of gastric cancer than any other. Based on these findings, the authors concluded that green tea may disrupt gastric carcinogenesis at both the intermediate and the late stages. [94]

Since 1990, researchers from Japans National Cancer Centres Epidemiology and Prevention Division have followed have followed 72,943 subjects cohort (34,832 men and 38,111 women) in what is known as the Japan Public Health Centre-based prospective study. Subjects were asked to reply to a lifestyle questionnaire, covering sociodemographic characteristics, medical history, smoking habits and diet (33 food items were assessed), as well as drinking habits for green tea, black tea, and coffee. Between 1990 and 2000 there were 892 cases (665 men and 227 women) of gastric cancer diagnosed. The results of this study showed that whilst no association between green tea consumption and gastric cancer was observed among men, a decreased risk of gastric cancer was observed among women; in fact, women who consumed 5 or more cups per day had a reduced risk of distal gastric cancer of almost 50%. [95]

In 1984, a total of 26,311 residents in northern Japan (11,902 men and 14,409 women 40 years of age or older), completed a self-administered questionnaire that included questions about the frequency of consumption of green tea. Between 1984 and 1992, a total of 419 cases of gastric cancer (in 296 men and 123 women) were diagnosed among these residents. The results of this study found no association between green-tea consumption and the risk of gastric cancer. It should however be mentioned that this same cohort (group of residents) did not show any association between green tea and breast cancer either, whereas the majority of other epidemiological studies did. This suggests that perhaps there was some other confounding factor among this particular population of residents in rural northern Japan that was different from the other population studies. [96]

A population-based case-control study was conducted involving 133 stomach cancer cases, 166 chronic gastritis cases, and 433 healthy controls among citizens of Yangzhong City, an island situated on Yangtze River southeast of China. [97] The people of Yangzhong are known for having one of the highest rates of cancers of the digestive tract. Cases and controls were interviewed using a standard epidemiological questionnaire which examined demographic factors, occupational history, medical history, family history of digestive cancers, dietary habits (including tea intake), smoking and alcohol drinking history, body weight and height etc. Patient medical records were also examined. Not surprisingly, it was found that more smokers and alcohol drinkers were found among stomach cancer cases than among the healthy controls. A protective effect of green tea was observed in stomach cancer; in fact, with increased frequency of green tea drinking and years of green tea drinking, a decreased risk of stomach cancer was shown. Green tea drinkers had a 48% reduced risk of stomach cancer than non-drinkers; in fact, those who consumed more than 21 cups per week decreased the risk by over 60%. Green tea drinking also showed protective effect against chronic gastritis, as green tea drinkers had a 50% reduced risk than non drinkers. This is an important discovery because chronic gastritis is known to frequently precede gastric cancer. [98]

A case control study conducted by Shanghai’s Fudan University compared 206 gastric cancer patients with 415 population controls. Green tea decreased the development of gastric cancer risk by 40%. Dose-response relationships were observed between the length of time, concentration and quantity of green tea drinking and its protective effects on gastric cancer. For individuals who drink green tea for more than 250 g per month, the risk of gastric cancer reduced about 60%. [99]

The largest prospective study to investigate the association between green tea consumption and the risk of stomach cancer death was a Japanese population-based prospective study known as the Japan Collaborative Cohort (JACC); a nation-wide multicentre prospective study which evaluated various risks on cancer incidence and mortality. [100] A total of 127 477 (54 032 men and 73 445 women) healthy citizens over 40 years old from 6 cities, 34 towns and five villages covering most of Japan, were enrolled in the study in 1990 after completion of a questionnaire, and followed until 1997. The surveys assessed the usual criteria including medical history, lifestyle-related questions such as diet, physical activity, drinking and smoking, occupation, level of education, reproductive history, family medical history etc. In total, 30 370 men and 42 481 women were asked whether they drank green tea, and if they did, how frequently they consumed it. By the end of the study, 240 men and 119 women had died of stomach cancer. The results showed that there was no association between the consumption of green tea and the risk of stomach cancer death among men. Women who consumed 5-9 cups per day had 20% less deaths from stomach cancer, and those who consumed more than 10 had 30% less stomach cancer.

Although this shows some protective effect, it is not considered statistically significant. Although this was the largest prospective study to examine the association between green tea consumption and stomach cancer deaths, there were several problems with this study that may account for the contradictory findings. First of all, the proportions of smokers were higher among those who consumed more green tea for both men and women. Because smoking can cause cancers of the upper digestive tract, this may have caused high green tea consumers to have more cancers than what they would have had they not have smoked. Although smoking was controlled for in the statistical analysis, this higher proportion of smokers may have significantly affected the outcome.

Secondly, the people who recorded being highest consumers of green tea also recorded being higher consumers of everything. Therefore it is possible that these people were likely to over estimate their actual intakes.

Another important factor which may have affected these results was discussed by the authors:

“In Japan, tea is usually made in china pots with hot water (about 80°C) and not only are the first extracts consumed, but also the second and/or the third as well. The effective components of green tea such as polyphenols might be insufficient in the second and/or third extracts. If high consumption of green tea (>=10 cups per day) were protective against stomach cancer, the Japanese custom of drinking second/third extracts would be less effective in the prevention of stomach cancer.”

The authors also note that:

“Another possible limitation was that we did not obtain information on the presence or absence of a history of infection with Helicobacter pylori, a strong risk factor for stomach cancer.”

They suggest that it is unlikely that the prevalence of infection was higher among the subjects with a high consumption of green tea, however because they never assessed infection rates, it can never be known whether or not this may have affected the results. For example, there were 9 women who died of gastric cancer that consumed >10 cups per day. If even a few of these women had been infected with H.pylori, it could have significantly affected the outcome. Due to the authors’ failure to ascertain this important detail, one can only speculate. Further studies examining the relationship between green tea consumption and gastric cancer should ensure that H.pylori infection rates are controlled for. In Conclusion Evidently the results of human trials are mixed.

All of the case control studies found a protective effect among green tea drinkers, whereas all but one of the prospective cohort studies did not find his association. It could be argued that the case-control studies give a more accurate result because they examined a larger number of gastric cancer cases than did the prospective cohorts; however both types of studies have their strengths and weaknesses, and it is generally agreed that prospective cohort studies have the better design. More human studies using careful methodologies are needed before any definite conclusion can be reached regarding the association between green tea consumption and gastric cancer.

Lung Cancer  

In Vitro  

Green tea has shown success inhibiting lung cancer growth in vitro. [101] It has also shown to enhance the effects of chemotherapy drugs used to treat lung cancer such as tamoxifen. [102]

Animal Studies

• 1992: Aviano Cancer Center, Italy: The tumour suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Individuals with this gene (Li-Fraumeni syndrome), who routinely have a germline mutation in the p53 tumor suppressor gene, are at high risk for lung cancer, confirming its intimate role in lung tumorigenesis in humans. In fact, recent evidence indicates that individuals with a p53 germ-line mutation (Li-Fraumeni syndrome) have a 50% risk of developing lung cancer by age 60. In this experiment, mice with a mutation in the p53 gene that were treated with green tea displayed an average of 50% inhibition of lung tumours compared to those not given green tea. [103]

• 1992: American Health Foundation: Mice were given either ordinary drinking water, 2% green tea, 560 ppm EGCG or 1120 ppm caffeine in their drinking water for 13 weeks. During this time, NNK was administered by gavage three times weekly for 10 weeks from weeks 3 to 12. Five weeks later they were killed and examined. Mice treated with NNK developed 22.5 lung adenomas per mouse, whereas NNK-treated mice that drank green tea or EGCG as drinking water developed only 12.2 and 16.1 tumours per mouse, respectively. Both green tea and ECGC suppressed the increase of 8-OH-dGuo (a product of DNA damage indicating carcinogenesis.[104,105]) levels in mouse lung DNA. The authors concluded:

  “Because 8-OH-dGuo is a DNA lesion caused by oxidative damage, these results suggest that the mechanism of inhibition by green tea and EGCG in NNK-induced lung tumorigenesis is due at least partly to their antioxidant properties.”[106]

• 1994: Rutgers University: When decaffeinated green or black tea extracts were given to female A/J mice as the sole source of drinking fluid before an injection of NNK, a significant reduction in lung tumor multiplicity was observed.[107]

• 1995: West China University of Medical Sciences: Lung cancer was induced in rats by exposing them to Crocidolite (Blue Asbestos) plus benzo(a)pyrene. The incidence of lung cancer was lower, and the survival time of the first case of cancer and the average survival time of the rats with lung cancer were higher in the group of rats drinking 2% green tea extract for life than in the group that did not drink green tea extract.[108]

• 1997: Academy of Military Medical Sciences, Beijing: C57/BL6J mice were inoculated with Lewis lung cancer cells as an experimental model to study the effects of green tea on cancer prevention, inhibition of tumour growth and immune regulation in mice with tumour. The examination of various biological markers indicated that green tea had no obvious inhibition in Lewis lung cancer and protective effects, to various extents, on adverse changes measured in this experiment. [109] This study did not however actually examine tumour incidence, but instead measured various indices associated with tumour growth such as thymus function etc. What’s more, as mentioned already, experiments using mice which have been inoculated with cancer cells may give some indication of the ability to affect tumour growth, but it does not determine whether or not prevention of the cancer is possible to begin with.

• 1998: Rutgers University : Green tea inhibited N-nitrosodiethylamine-induced lung tumour incidence and multiplicity in female A/J mice when tea was given either during the carcinogen treatment period or during the post-carcinogen treatment period. In a separate tumorigenesis (the beginning of tumour growth) model, both decaffeinated black tea and decaffeinated green tea inhibited (NNK)-induced lung tumour formation. The authors suggest that the anti-carcinogenic actions of tea may be due to its antiproliferative effects. [110]

• 2001: Taipei Medical University: EGCG alone reduced lung metastases in mice with melanomas. However, a combination of EGCG and dacarbazine (a drug used to treat melanomas) was more effective than EGCG alone in reducing the number of pulmonary metastases and primary tumor growths, and increased the survival rate of melanoma-bearing mice.[111]

• 2000: University of California: Green Tea did not prevent lung cancer in mice exposed to mixture of cigarette side-stream and mainstream smoke for 6 hours a day, 5 days a week, for 5 months. This is not terribly surprising as considering the size of a mouse, 6 hours a day worth of smoke inhalation would be extremely carcinogenic and not representative of the exposure that humans would be likely to encounter. [112]

• 2001: National Institute of Health Sciences, Tokyo: male rats were exposed to 1,2-dimethylhydrazine, or 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for two weeks. They then received diet containing 1 or 0.1% green tea catechin or a normal diet alone for 33 weeks after which time they were killed and examined. Incidences and/or multiplicity of lung hyperplasia and tumours, and thyroid lesions did not significantly vary between the different groups. The number of colon carcinomas and the average size of colon tumours were significantly increased in the rats given 0.1% green tea catechins, whilst a similar yet less significant tendency occurred in the rats given 1% green tea catechins. The authors concluded:

  “These results indicate that GTCs do not inhibit, but rather may enhance colon carcinogenesis, while not influencing lung and thyroid carcinogenesis under the present experimental conditions.” [113]

Like several of the other animal studies which did not find a cancer preventing effect from green tea, these rats were not given green tea during the time they were exposed to chemical carcinogens, but after. The majority of experiments in which rats were given green tea throughout the time they were exposed to cancer causing chemicals show green tea to have a cancer preventing effect. If one were to extrapolate this to human circumstances, long term consumption of green tea would be more likely to show a cancer preventing effect than consumption later in life after which time exposure to cancer causing agents may have already occurred.

• 2004: The Sate University of New Jersey: Mice exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a chemical carcinogen used to cause lung cancer growth, were then given either 0.1, 0.2, 0.4, and 0.6% green tea solution, 0.02% caffeine, or water as the sole source of drinking fluid until the termination of the experiment. At the end of the trial, the mice were killed and their lung tissues were examined. Only the mice given 0.6% green tea solution (the strongest dose) had significantly decreased lung tumour multiplicity (the number of tumours per mouse). The mouse given the strongest dose of green tea also showed inhibited angiogenesis (the increased growth of blood vessels which feeds a tumour). Tumours cause an increase in angiogenesis so that they can have an increased nutrient supply; consequently, reducing angiogenesis can significantly inhibit the growth of the tumours. The mice given the highest green tea dose also had significantly lower vascular endothelial growth factor immunostaining scores. The mice given the highest green tea dose also had significantly higher apoptosis of the lung tumours as well. (Apoptosis is a normal cell death; a function which fails in cancerous cells. Causing apoptosis to occur in tumour cells can significantly inhibit the growth of the tumour.) The authors concluded:

  “Inhibition of angiogenesis and the induction of apoptosis by green tea may be closely related to the inhibition of pulmonary carcinogenesis.” [114]

• 2004: University of Tennessee: For 10 days, hamsters exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; a nicotine-derived nitrosamine, which is formed during tobacco smoking. It is a chemical carcinogen used to induce lung cancer.) They were then treated with either green tea or theophylline (a drug used to dilate the air ways.) Both significantly inhibited lung tumour multiplicity (the number of tumours in each hamster) of neuroendocrine tumours, however both also significantly promoted the lung tumour multiplicity of adenocarcinoma’s (a different type of lung cancer). These results suggested that green tea can either inhibit or actually promote lung cancer, depending on the type of tumour involved. The authors concluded:

  “At the current state of knowledge such chemopreventive treatments should only be used as adjuvant to cancer therapy of cancers that have been fully characterized at the pathology and molecular level.” [115]

This means that until further evidence has been established, persons (and hamsters) diagnosed with pulmonary adenocarcinomas caused by smoking may be best to avoid large dioses of green tea extract.  

Human Studies

In 1990, researchers in from Germany collected epidemiological and experimental materials from the Chinese population in Hong Kong. In a retrospective study of 200 female lung cancer patients and 200 matched controls, all subjects were interviewed concerning their eating habits, smoking histories, and lifetime exposures to environmental pollutants. Analysis of the data demonstrated an increased lung cancer risk of among those who drank green tea, however an analysis of several popular brands of green tea in Hong Kong found significantly elevated levels of mutagenic activity. [116] Similar results have not been found elsewhere.

One particular type of screening shown to have potential in detecting cancer risk is to examine the rate of Sister Chromatid Exchange in lymphocytes [117] (white blood cells), because SCE rate is enhanced when exposed to carcinogens (substances that cause cancer) and mutagens (substances that cause irregularities in DNA which may lead to cancer).

In 1997, researchers from the Ministry of Health and Welfare, Korea, obtained blood specimens were from non-smokers, smokers, smokers consuming green tea (3 cups/day), and smoker/coffee drinkers. The frequencies of sister-chromatid exchange (SCE) in mitogen-stimulated peripheral lymphocytes (white blood cells which have started to undergo cellular division) from each experimental group were determined and analyzed. Because cigarette smoke is both carcinogenic and mutagenic, it was no surprise to find that SCE rates were significantly elevated in smokers compared to that of non-smokers; however, the frequency of SCE in smokers who consumed green tea was similar to that of non-smokers, implying that green tea can block the cigarette-induced increase in SCE frequency. Coffee, by contrast, did not exhibit a significant inhibitory effect on smoking-induced SCE. [118]

A population-based case-control study conducted in China examined the association between past consumption of green tea and the risk of lung cancer. A total of 649 female lung cancer patients and 675 age matched controls were interviewed between 1992 and 1994, and among other questions, green tea consumption as well as smoking history were assessed and compared. Among non-smoking women, consumption of green tea was associated with a 35% reduced risk of lung cancer, and the risks decreased with increasing consumption. Little association was found among women who smoked. [119]

In Conclusion

Whilst there is some good evidence to suggest that green tea consumption may help to prevent lung cancer, particularly in animals, human data is lacking. More human studies are needed to establish whether any correlation between green tea and lung cancer exists.

Prostate Cancer

In vitro

Prostate cancer cells have demonstrated enhanced apoptosis and growth inhibition after exposure to EGCG in vitro.[120]

Animal Studies

• 2003: Harvard Medical School: Mice inoculated with human prostate cancer cells were given one of 6 different combinations of diets including green tea, soy phytochemicals and black tea. 10 weeks later the mice were killed and examined. Green tea alone did not affect prostate tumour growth, but when in combination with soy phytochemical concentrate synergistically inhibited final tumour weight and metastasis and significantly reduced serum concentrations of both testosterone and dihydrotestosterone (DHT). Soy plus black tea also showed a similar effect, but no effect was seen in either food substance alone, suggesting that combinations of tea and soy may be more effective at inhibiting prostate cancer than either one alone.[121]

• 1995: University of Chicago: Injections of different catechins (including ECGC) on the growth of human prostate cancer cells were studies in nude mice (mice without the ability to produce T cells, specifically bread so that they can not reject tumours or transplants on their own). The injection of EGCG slowed the growth of tumours when injected into the control mice after two weeks, whilst the growth of tumour accelerated when EGCG was stopped in the treatment group after 2 weeks. EGCG was the only effective catechin at inhibiting tumour growth. Because the frequency of the latent, localized type of prostate cancer does not vary significantly between Eastern and Western cultures, but the clinical incidence of metastatic prostate cancer is generally low in Japan and other Asian countries, the authors concluded:

  “It is possible that there is a relationship between the high consumption of green tea and the low incidence of prostate and breast cancers in some Asian countries.” [122]

• 2001: Case Western Reserve University & the Research Institute of University Hospitals of Cleveland. The effects of green tea was examined in a type of mouse model that closely resembles human prostate cancer called Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP), used specifically because it mimics progressive forms of the human disease. The mice with TRAMP which were fed green tea had a decline in the overall incidence of tumour development as well as a decreased tumour burden and a decreased incidence of distant metastases compared with those which were not fed green tea. [123]

• 2004: University of Wisconsin The effects of green tea polyphenols on a protein called insulin-like growth factor-1 (IGF-1) were examined in mice, because men with prostate cancer have been found to have increased levels of IGF-1. The results showed that the mice that received the green tea had lower levels of IGF-1 by comparison with those not feed green tea. This and other studies have found that green tea appears to stall cancer cell growth by decreasing production of several proteins that promote cell survival as well as reducing the production of proteins that are known to be associated with the spread of cancer cells. This study also found that green tea appeared to starve prostate cancer tumour cells by inhibiting angiogenesis (the formation of blood vessels), thereby suppressing the flow of nutrients to the cancerous cells. [124]

• 1999: Case Western Reserve University : The development and growth of both normal and cancerous prostate cells are regulated by androgens (steroid hormones such as testosterone that control masculine characteristics). [125] An enzyme called ornithine decarboxylase (ODC) which is an “androgen-responsive gene”, (that is, its expression is regulated by androgen levels) is over-expressed in prostate cancer and prostatic fluid in humans. [126] Therefore, it is thought that approaches aimed at modulating ODC may be effective at preventing prostate cancer. [127] This study investigated the effect of green tea polyphenols against the induction of ODC (mediated by testosterone) in human prostate cells both in vitro (cell cultures), in mice and rats. As expected, treating the cells in vitro with testosterone induced ODC in a dose dependent-manner. Pre-treating the cells with green tea polyphenols however inhibited the testosterone from inducing ODC activity in a dose-dependent manner (the more green tea polyphenols used, the more effective the inhibition of ODC). Treating the cells with testosterone also significantly increased the level of ODC mRNA, whereas this did not occur when the cells were pre-treated with green tea polyphenols. [128]

• Both castrated and non-castrated rats were fed either 0.2% polyphenols in their drinking water or just plan drinking water for 7 days, prior to being injected with testosterone. ODC activity increased 38-fold in the prostate of castrated rats and 2-fold in that of non-castrated ones. The castrated rats which had been feed green tea polyphenols had 54% less testosterone-caused ODC activity than those given plain water, whilst the non-castrated rats fed green tea polyphenols showed 20% less ODC activity.Similar results occurred with mice, where testosterone treatment at similar dosage resulted in a 2-fold increase in ODC activity in the prostate. Prior feeding with 0.2% green tea polyphenols resulted in 40% inhibition in this induction.[128]

• Green tea Polyphenols have also inhibited ODC induction caused by tumor promoters in mouse skin and other tissues.[129-132]

Human Studies

Little epidemiological evidence regarding green tea and prostate cancer is available, as the majority of studies examining tea intake and prostate cancer have looked mostly at black tea.

The results of a prospective cohort study involving 7,833 men of Japanese ancestry clinically examined from 1965 to 1968 were published in 1986. Black tea was shown to have a slightly protective influence on prostate cancer, but significantly increased the risk of rectal cancer. [133]

The relationship between prostate cancer and beverage intake was examined in a case-control study conducted in 3 areas of Canada ( Ontario, Quebec and British Columbia). Complete beverage intake history of 617 men with prostate cancer were compared to 637 population controls (men without prostate cancer). The results showed a 30% decrease in risk was with tea intake of more than 500 g per day, however this included both black and green tea. [134]

Two years later in 2000, a retrospective cohort study among Canadians also examined the relationship between beverage intake and prostate cancer risk. The mortality and cancer experience of male participants aged 50-84 years was determined between 1972 - 1993. Among the 3400 survey participants included in the study, 145 developed prostate cancer. No association was observed between tea intake and prostate cancer; in fact, who drank more than 500 ml of tea per day experienced virtually the same risk as those who reported no tea consumption. It should be noted however that tea consumption among these participants was predominantly black tea.[135]

Recently, researchers from Curtin University of Technology Information in Australia conducted a case-control study which looed at the relationship between green tea consumption and prostate cancer in Hangzhou, southeast China. Information on duration, quantity and frequency of usual green tea consumption, as well as the number of new batches brewed per day, were collected by face-to-face interview of 130 men with prostate cancer and compared to 274 age matched controls. It was found that prostate cancer risk declined with increasing frequency, duration and quantity of green tea consumption. Green tea drinkers had a 70% reduced risk of prostate cancer. Consuming more than 3 cups per day reduced the risk by approx 70%, consuming green tea for more than 40 years reduced the risk by almost 90%, whilst consuming more than 1.5 kg of tea leaves yearly decreased the risk by more than 90%. [136]

Prostate cancer is often detected or monitored by prostate specific antigen levels. Prostate specific antigens (PSA) are proteins that are normally produced by the prostate and can be detected in circulating blood. Elevated PSA levels may indicate the presence of cancer and are utilized to determine efficacy of treatment in patients with previously diagnosed prostate cancer. [137]

A recent clinical trial conducted by researchers at the Mayo Clinic and the North Central Cancer Treatment Group involved 42 men with advanced, hormone-resistant prostate cancer. Patients were instructed to take 6 grams of green tea per day orally in 6 divided doses, which is approximately equivalent to 6-12 cups per day. The men’s PSA levels were recorded monthly to assess how effective the treatment was. After one month, only one patient’s PSA levels had decreased (by 50%) however this only lasted for another month. The PSA levels of the other 41 patients actually increased by more than 40% after the first month of treatment. Nearly all the men experienced uncomfortable side effects fro the green tea such as nausea, emesis, insomnia, fatigue, diarrhoea, abdominal pain, and confusion. The authors concluded:

“Green tea carries limited antineoplastic activity, as defined by a decline in PSA levels, among patients with androgen independent prostate carcinoma.”[138]

There have been several common criticisms made of this study. Firstly, there was little reason to suspect that green tea would be able to treat advanced hormone resistant prostate cancer to begin with. It is not terribly surprising that this treatment was not effective, however it can not be concluded that green tea consumption would not be able to prevent prostate cancer from occurring in the first place.

It should also be mentioned that this trial was not controlled; that is, there was no placebo group with which to compare the results. Consequently, it can not be known what effect NOT taking green tea may have had on PSA levels. A better methodology used to test the effectiveness of treatments measured by biomarkers is the double blind placebo controlled trial, particularly when the subjects cross over; that is, that after a certain period of time, the patients taking the placebo start taking the treatment whilst those on the treatment start taking the placebo. (Double blind of course means that neither the patients nor the person administering the treatment knows whether it is the placebo or not that they are taking.). In a controlled trial, the results shown by the treatment can be compared to that shown with no treatment (placebo) but with nothing to compare with, conclusions are less clear.

Esophageal Cancer

Animal Studies

• 1992: Chinese Academy of Preventive Medicine: In the first experiment, rats were given two precursors of the carcinogen NMBzA, (sodium nitrite and methyl benzylamine). After 12 weeks, the incidence of esophageal tumours was 95% in rats not given tea; however the incidence in those given either green tea, jasmine tea, black tea, or oolong tea, the incidences were only 5-19%. In the second experiment, preformed NMBzA was given to the rats. The incidence of esophageal cancer in those not given tea was 90%, whereas the incidence in those given either of the 5 different teas was only 42-67%.[139]

• 1995: Rutgers University : Rats were treated with the carcinogen N-nitrosomethylbenzylamine (NMBzA) for 5 weeks; 39 weeks after the initial dose of NMBzA, 65% of the rats had esophageal tumours. In the groups of rats receiving 0.6% of decaffeinated green tea or decaffeinated black tea as the sole source of drinking fluid during the NMBzA-treatment period, esophageal tumor incidence and multiplicity were reduced by approximately 70%, whereas in the rats given tea after the NMBzA treatment period, the esophageal tumour incidence and multiplicity were reduced by approximately 50%. A second experiment involved giving the rats either regular green tea or decaffeinated green tea whilst being treated with NMBzA. After the NMBzA treatment period, tumour multiplicity was decreased by > 55% in the rats receiving either form of green tea, however the rats receiving regular green tea, the volume per tumour was reduced by approximately 60%. The blood and urine levels of green tea polyphenols due to tea administration were determined in these rats, and the levels were comparable to those in humans after tea consumption. [140]

• 1996: Institute of Cancer Research, Chengdu: Rats were given either 2% green tea solution or water for 24 weeks. After 4 weeks, all rats were injected with the carcinogen MANA, weekly for 20 weeks. he animals were sacrificed at 4 intervals. The incidence rates of esophageal cancer in the rats of the two groups sacrified at every interval were significantly different. The result suggested that green tea should have a preventive and blocking effect on the occurrence of esophageal cancer in rats.[141]

• 1997: Ohio State University School of Public Health : A highly mutagenic nitrosamine chemical called N-nitrosomethylbenzylamine (NMBA) is specific in inducing tumours in the esophagus of rats. Rats given NMBA which had green tea in their water had a slight reduction of esophageal tumour incidence, but the reduction was greater in those given high doses of EGCG. [142]

• 2004: This study found that replacing the rats drinking water with green tea after having been injected with NMBA significantly reduced is mutagenic effect; consequently inhibiting its carcinogenic (cancer causing) effect. [143]

Human Studies

Medical records of patients aged 30-74 years old who were diagnosed with esophageal cancer between 1990 and 1993 were identified from the Shanghai Cancer Registry, which covers 6.8 million people in the urban area of Shanghai, China. During this time, records of 1016 patients with esophageal cancer were identified, among which 902 were interviewed to obtain information on demographic characteristics, residential history, height and weight, diet, smoking, alcohol and tea drinking, medical history, family history of cancer, occupation, physical activity, and reproductive history. A total of 1552 control subjects (people without esophageal cancer) were also interviewed and the results of their data was compared with the esophageal cancer patients. It was found that green tea consumption decreased the risk of esophageal cancer among women by 50%; in fact, The more green tea consumed, the more protection was observed. No significant difference was found among men. Among those who did not smoke or drink alcohol however, green tea consumption decreased the risk of esophageal cancer by approximately 60% in both men and women. [144]

It is well established that the Henan province is the highest incidence area for Esophageal Cancer in the world. In a recently published intervention trial, 200 subjects with different severity of esophageal precancerous lesions were given either 5mg of de-caffeinated green tea daily or a placebo. After a year, patients taking decaffeinated green tea did not show apparent difference between the treatment and placebo group in alleviating the esophageal precancerous lesions and abnormal cell proliferation. [145] These results are not terribly surprising given the results of a small study at the State University of New Jersey in 1999, which showed that catechins were found in the saliva when subjects drank tea (in even higher concentrations when holding a tea solution in the mouth for a few minutes without swallowing) whereas taking tea solids in capsules resulted in no detectable salivary catechin level. The authors concluded:

“….slowly drinking tea is a very effective way of delivering rather high concentrations of catechins to the oral cavity and then the esophagus.” [146]

Because the participants in the intervention trial were taking green tea as a pill and not as a liquid, their esophageal tissue would not have been exposed to adequate cathechin levels to have any significant effect.

In the Jiangsu Province of China, a case-control study on 209 cases of upper digestive tract cancer was conducted 129 males and 80 females aged 35-79, 68 of which had esophageal cancer. It was found that pickled vegetables significantly increased the risk of all upper digestive tract cancers, whereas green tea significantly decreased the risk of both esophageal cancer (80% reduction) and other gastric cancers (70% reduction). Fruit consumption was also associated with a 50% reduced risk. [147]

Another case control study in the same area of China involved 206, 204 and 218 patients with gastric cancer, liver cancer, esophageal cancer, all of which were alcohol drinkers and smokers. Green tea drinking seemed to have decreased 81%, 78%, 39% risk for the development of gastric cancer, liver cancer and esophageal cancer among alcohol drinkers. It might also have decreased 16%, 43%, 31% on the risks of developing the three kinds of cancers among cigarette smokers. [148]

A massive cohort study followed 220,272 men and women aged 40 to 69 in Japan, between 1966 and 1981, of which 440 died of esophageal cancer. Drinking scalding hot green tea as apposed to drinking tepid green tea actually increased the risk of esophageal cancer by 60%. It was thought that the thermal effects of the hot tea contributed to the increased esophageal cancer rates than the tea itself. [149] Other studies have also found higher rates of esophageal cancer among people who consume scalding hot foods and drinks. [150,151]

Skin Cancer

In vitro

In recent in vitro studies, when EGCG was applied to both melanoma (skin cancer) cells and normal skin cells called melanocytes, it was found to result in a dose-dependent decrease in the viability and growth of the melanoma cells without affecting the normal cells. EGCG also caused a decrease in proliferation of the cancerous cells, it was able to induce apoptosis (normal cell death which ceases to occur in cancerous cells), it significantly inhibited the colony formation ability of the cancer cells and had favourable affects on the regulation of Bcl2 protein (which controls the rate of apoptosis) regulation. Furthermore, EGCG demonstrated favourable dose-dependant effects on the expression of certain proteins involved cell death called cyclin kinase inhibitors. [152]

When applied to aged skin, EGCG stimulated the proliferation of epidermal keratinocytes , as well as inhibiting UV-induced apoptosis (cell death caused by the suns radiation) as well as having favourable effects on protein expression which controls cell death. It was thus proposed that these mechanisms may help to decrease UV damage to skin and protect it from melanoma. [153]

When the skin is exposed to various stimuli which cause inflammation, production of substances called eicosanoids are produced, which are known to contribute to the process of tumour promotion. A type of enzyme called COX-2 is known to occur in several types of malignant skin cancers; in fact, increased COX-2 has been seen to occur in the skin cancer in mice and humans after being exposed to cancer-causing doses of ultra violet (B band) radiation. When both human skin and mouse skin were exposed to high doses of UVB radiation , (the type of radiation emitted by the sun) COX-2 expression increased significantly in them both. When both human and mouse skin had green tea extract topically applied to it, the increase in COX-2 was largely abrogated, signifying that green tea extract had a considerable anti-carcinogenic effect on UVB-induced skin cancer. [154]

Several other studies have also shown that topical application of green tea extract has the potential to protect skin cells against skin cancer caused by UVB radiation. [155,156]

Animal Studies

• 1991: Case Western Reserve University : The effect of oral feeding and topical application of green tea polyphenols on ultraviolet B (UVB) radiation-induced skin carcinogenesis in hairless mice was assessed in this study. Long-term feeding of green tea polyphenols (0.1%, w/v) in drinking water resulted in significantly lower tumour yield (percent of animals with tumours and number of tumours per mouse) and as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also afforded protection against photocarcinogenesis (cancer caused by ultraviolet light); however, the protective effect was lower than that which occurred in the rats fed green tea polyphenols in their drinking water. [157]

• 1992: State University of New Jersey : Female mice were either given either green tea extract as their sole source of drinking water, or just plain water. They were then exposed to ultraviolet B light (UVB) once daily for 7 days , which resulted in red sunburn lesions of the skin. The intensity of red colour and area of these lesions were inhibited in a dose-dependent fashion in those that consumed green tea. In a different experiment, female mice were exposed to UVB radiation once daily for 10 days followed 1 wk later by twice weekly application of the chemical carcinogen 12-O-tetradecanoylphorbol-13-acetate for 25 wk, which resulted in the development of skin tumours. Once again, the formation of skin tumours was inhibited in the mice that consumed green tea during this time. In yet another experiment, female mice were treated with the chemical carcinogen 7,12-dimethylbenz(a)anthracene, followed 3 weeks later by irradiation with significantly stronger doses of UVB radiation than in the prior experiments for 30 weeks. Once again, UVB-induced formation of skin tumors and this time even increased spleen size were inhibited by the green tea extract as the sole source of drinking water prior to and during the 30 wk of UVB treatment. [158]

In these experiments, treatment of the animals with the green tea extract not only decreased the number of skin tumours but also decreased substantially the size of the tumours. In additional studies, mice were initiated by topical application of the carcinogen DMBA followed by twice weekly application of the chemical carcinogen TPA for 25 weeks. Yet again, the green tea extract as the sole source of drinking water during this time reduced the number and incidence of skin tumours.These experiments used a 1.25% green tea extract (1.25 g of tea leaves/100 ml of water) which contained 4.69 mg of green tea extract solids per ml , because this is similar in composition to green tea beverages consumed by humans.

• 1993: Case Western Reserve University : The effect of green tea polyphenols on both stage I and stage II skin tumour promotion in mice was assessed, as well as the effect of its duration. Topical application of green tea polyphenols whilst being treated with either TPA or mezerein in stage I or stage II respectively, resulted in significant protection against skin papilloma formation in terms of both tumour multiplicity (42-50%) and tumour growth (43-54%).More profound and sustained protective effects of green tea polyphenols were evident when it was applied continuously during both stage I and stage II of the skin tumour promotion period. A 71%, 37% and 74% protection in terms of tumour multiplicity, tumour incidence and tumour growth, respectively was shown among the mice treated with green tea continuously compared to those not treated with green tea at all. [159]

• 1994: State University of New Jersey : Female mice were given either black tea, green tea, decaffeinated black tea, or decaffeinated green tea as the sole source of drinking fluid 2 weeks prior to and during 31 weeks of UVB radiation exposure. Administration of all the different tea preparations not only inhibited the number of tumours, but tumour size was also markedly decreased. The number of carcinomas (malignant tumours) per mouse was inhibited by 93, 88, 77, or 72%, respectively. [160]

• 1996: Arizona Cancer Center : Topical applications of EGCG to mice significantly reduced skin cancer development after being exposed to UVB Radiation by comparison with those not treated with EGCG. Oral administration of EGCG in themices drinking water however did not provide the same protective effect. [161]

• 1997: The State University of New Jersey : Feeding green or black tea inhibited UVB light-induced skin cancer formation in mice though green tea was a more effective inhibitor than black tea. Decaffeinated teas however did not have a protective effect; in fact, caffeine alone showed some protective effect whilst large doses of decaffeinated teas actually had a harmful effect.[162] The authors concluded:

  “The results indicate that caffeine contributes in an important way to the inhibitory effects of green and black tea on UVB-induced complete carcinogenesis.”

• 1997: Case Western Reserve University : Green tea polyphenols were topically applied on mouse skin prior to TPA treatment initiated by DMBA. After 20 weeks, treatment with green tea polyphenols resulted in significant protection against skin tumour promotion in terms of tumour incidence (32-60%), multiplicity (49-63%) and tumour volume per mouse (73-90%). [163]

• 1998: CSIRO: Mice were exposed to UVB radiation and either given water to drink, green and black tea with milk added, or tea without milk. The mice which drank the tea with milk added had 50% fewer tumours, and 55% smaller lesions than mice consuming water only. Mice consuming tea without milk had fewer papillomas and tumours than mice consuming tea with milk; however, the difference in area affected was not statistically significant.[164]

• 1998: Osaka Kun-Ei Women's College: Chlorophyll a and b (the green pigments) from green tea showed significant suppression in a dose-dependent manner on skin cancer development in mice treated with the tumour promoter TPA initiated by the carcinogen DMBA.[165]

• 1998: A similar experiment was carried out by the same researchers as mentioned above. When Pheophytin a and b, (chlorophyll related compounds that are not polyphenols) in green tea were topically applied to mice prior to treatment with TPA initiated by DMBA, they caused suppression in a dose-dependent fashion against skin tumorigenesis, they exhibited significant suppressions against TPA-induced inflammatory reaction such as edema formation, as well as inhibiting effects against induction of ornithine decarboxylase (ODC). [166]

• 2001: The State University of New Jersey: When hairless mice were given green or black tea orally after being treated with UVB radiation, the number of tumours per mouse was significantly decreased after 23 weeks in comparison with those not given tea. Those given decaffeinated tea however did not show this same effect, however those given only caffeine showed a protective effect as well. It was thought that perhaps the caffeine may have helped to prevent the occurrence of skin cancers due to its ability to reduce the amount of tissue fat beneath the skin. [167]

HUMAN STUDIES:

An 8-year prospective cohort study of 35,369 postmenopausal women in Iowa found that drinking more than 2 cups of tea per day reduced the risk of digestive tract cancers by 30% and urinary tract cancers by 60%, however found no association with melanoma. It should be noted however that the majority of tea consumed was black tea. [168]

No population studies have looked at green tea in relation to skin cancer; however the clinical trials that have shown skin protection from green tea provide at least preliminary evidence for its efficacy.

 

 

REFERENCES

[1] Stoner G and Mukhtar H: “Polyphenols as cancer chemopreventive agents.” J Cell Biochem Suppl 22,169 180,1995.

[2] Graham H. “Green tea composition, consumption, and polyphenol chemistry.” Prev Med 21, 334-350, 1992.

[3] McKay DL and Blumberg JB. The role of tea in human health: an update. J Am College Nutr 21(1): 1-13, 2002.

[4] Mukhtar H and Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr 71(suppl): 1698S-1702S, 2000.

[5] Yang C, Chung J, Yang G, et al. Tea and tea polyphenols in cancer prevention. J Nutr 130: 472S-478S, 2000.

[6] Chung F-L, Wang M, Rivenson A, et al.. Inhibition of lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen: caffeine as an important constituent. Cancer Res 58: 4096-4101, 1998.

[7] Katiyar SK and Mukhtar H. Tea in chemoprevention of cancer: epidemiologic and experimental studies (review). Int J Oncol 8: 221-238, l996.

[8]Yang CS and Landau JM. Effects of tea consumption on nutrition and health. J Nutr 130: 2409- 2412, 2000.

[9] Catterall F, Kassimi AI, Clifford MN, Ioannides C. Influence of milk on the antimutagenic potential of green and black teas. Anticancer Res. 2003 Sep-Oct;23(5A):3863-7.

[10] Yang CS, Lee MJ, Chen L. Human salivary tea catechin levels and catechin esterase activities: implication in human cancer prevention studies. Cancer Epidemiol Biomarkers Prev. 1999 Jan;8(1):83-9.

[11] Khafif A., Schantz S. P., Chou T.-C., Edelstein D., Sacks P. G. Quantitation of chemopreventive synergism between (-)-epigallocatechin and curcumin in normal, premalignant and malignant human oral epithelial cells. Carcinogenesis 1998;19:419-424[Abstract]

[12] Valcic S., Timmermann B. N., Alberts D. S., Wachter G. A., Krutzsch M., Wymer J., Guillen J. M. Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines. Anticancer Drugs 1996;7:461-468[Medline]

[13] Suganuma M., Okabe S., Kai Y., Sueoka N., Sueoka E., Fujiki H. Synergistic effects of (-)-epigallocatechin gallate with (-)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res 1999;59:44-47[Abstract/ Free Full Text]

[14] Yang G.-Y., Liao J., Kim K., Yurkow E. J., Yang C. S. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis 1998b;19:611-616[Abstract]

[15] Chen Z. P., Schell J. B., Ho C. T., Chen K. Y. Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts. Cancer Lett 1998;129:173-179[Medline]

[16] Valcic S., Timmermann B. N., Alberts D. S., Wachter G. A., Krutzsch M., Wymer J., Guillen J. M. Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines. Anticancer Drugs 1996;7:461-468[Medline]

[17] Katiyar SK. Skin photoprotection by green tea: antioxidant and immunomodulatory effects.Curr Drug Targets Immune Endocr Metabol Disord. 2003 Sep;3(3):234-42.

[18] Hibasami H., Achiwa Y., Fujikawa T., Komiya T. Induction of programmed cell death (apoptosis) in human lymphoid leukemia cells by catechin compounds. Anticancer Res 1996;16:1943-1946[Medline]

[19] Takada M, Nakamura Y, Koizumi T, Toyama H, Kamigaki T, Suzuki Y, Takeyama Y, Kuroda Y. Suppression of human pancreatic carcinoma cell growth and invasion by epigallocatechin-3-gallate. Pancreas. 2002 Jul;25(1):45-8.] [ Lyn-Cook BD, Rogers T, Yan Y, Blann EB, Kadlubar FF, Hammons GJ. Nutr Cancer. 1999;35(1):80-6.

[20] Sakata R, Ueno T, Nakamura T, Sakamoto M, Torimura T, Sata M. Green tea polyphenol epigallocatechin-3-gallate inhibits platelet-derived growth factor-induced proliferation of human hepatic stellate cell line LI90. J Hepatol. 2004 Jan;40(1):52-9.

[21] Ahmad N., Feyes D. K., Nieminen A.-L., Agarwal R., Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J. Natl. Cancer Inst. 1997;89:1881-1886[Abstract/ Free Full Text]

[22] Pillai SP, Mitscher LA, Menon SR, Pillai CA, Shankel DM. Antimutagenic/antioxidant activity of green tea components and related compounds.J Environ Pathol Toxicol Oncol. 1999;18(3):147-58.

[23] Cao G, Sofic E, Prior R. Antioxidant capacity of tea and common vegetables. J Agri Food Chem 44: 3426-3431, l996.

[24] Rice-Evans C, Miller N, Bolwell P, et al. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 22:375-383, l995.

[25] Benzie I, Szeto Y, Strain J, et al.. Consumption of green tea causes rapid increase in plasma antioxidant power in humans. Nutr Cancer 34:63-87, 1999.

[26] Sung H, Nah J, Chum S, et al. In vivo antioxidant effect of green tea. Eur J Clin Nutr 54:527- 529, 2000.

[27] Rice-Evans C, Miller N, Bolwell P, et al. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 22:375-383, l995.

[28] Lean M, Noroozi M, Kelly I, et al. Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA. Diabetes 48: 176-181, 1999.

[29] Hakin , IA , Harris, RB, Brown, S et al. Effect of increased tea consumption on oxidative DNA damage among smokers: a randomized controlled study. J Nutr; 133:33035S-3309S, Oct 2003.

[30] Khan SG, Katiyar SK, Agarwal R, Mukhtar H. “Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: possible role in cancer chemoprevention.” Cancer Res 52, 4050-4052, 1992.

[31] Ahmad N., Feyes D. K., Nieminen A.-L., Agarwal R., Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J. Natl. Cancer Inst. 1997;89:1881-1886[Abstract/ Free Full Text]

[32] Hibasami H., Achiwa Y., Fujikawa T., Komiya T. Induction of programmed cell death (apoptosis) in human lymphoid leukemia cells by catechin compounds. Anticancer Res 1996;16:1943-1946[Medline]

[33] Hibasami H., Komiya T., Achiwa Y., Ohnishi K., Kojima T., Nakanishi K., Akashi K., Hara Y. Induction of apoptosis in human stomach cancer cells by green tea catechins. Oncol. Rep. 1998;5:527-529[Medline]

[34] Okabe S., Suganuma M., Hayashi M., Sueoka E., Komori A., Fujiki H. Mechanisms of growth inhibition of human lung cancer cell line, PC-9, by tea polyphenols. Jpn. J. Cancer Res. 1997;88:639-643[Medline]

[35] Yang G.-Y., Liao J., Kim K., Yurkow E. J., Yang C. S. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis 1998b;19:611-616[Abstract]

[36] Suganuma M., Okabe S., Kai Y., Sueoka N., Sueoka E., Fujiki H. Synergistic effects of (-)-epigallocatechin gallate with (-)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res 1999;59:44-47[Abstract/ Free Full Text]

[37] Chen D, Daniel KG, Kuhn DJ, Kazi A, Bhuiyan M, Li L, Wang Z, Wan SB, Lam WH, Chan TH, Dou QP. Green tea and tea polyphenols in cancer prevention. Front Biosci. 2004 Sep 01;9:2618-31.

[38] Ahmad N., Feyes D. K., Nieminen A.-L., Agarwal R., Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J. Natl. Cancer Inst. 1997;89:1881-1886[Abstract/ Free Full Text]

[39] Dong Z., Ma W.-Y., Huang C., Yang C. S. Inhibition of tumor promoter-induced AP-1 activation and cell transformation by tea polyphenols, (-)-epigallocatechin gallate and theaflavins. Cancer Res 1997;57:4414-4419[Abstract]

[40] Lin Y.-L., Lin J.-K. (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-B. Am. Soc. Pharmacol. Exp. Ther. 1997;52:465-472

[41] Okabe S., Suganuma M., Hayashi M., Sueoka E., Komori A., Fujiki H. Mechanisms of growth inhibition of human lung cancer cell line, PC-9, by tea polyphenols. Jpn. J. Cancer Res. 1997;88:639-643[Medline]

[42] Xu Y, Ho CT, Amin SG, Han C, Chung FL (1992) Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 52: 3875–3879.

[43] Wang ZY, Hong JY, Huang MT, Reuhl KR, Conney AH, Yang CS (1992). Inhibition of N-nitrosodiethylamine-and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tomorigenesis in A/J mice by green tea and black tea. Cancer Res 52: 1943–1947.

[44] Cao Y, Cao R. Angiogenesis inhibited by drinking tea.Nature. 1999 Apr 1;398(6726):381.

[45] Lamy,S., Gingras,D. and Beliveau,R. (2002) Green tea catechins inhibit vascular endothelial growth factor receptor phosphorylation. Cancer Res., 62, 381–385.[Abstract/ Free Full Text]

[46] Hofmann,C.S. and Sonenshein,G.E. (2003) Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. FASEB J., 17, 702–704.[Abstract/ Free Full Text]

[47] Franceschi S, Barra S, La Vecchia C, Bidoli E, Negri E, Talamini R. A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin.Cancer Res. 2000 Feb 15;60(4):901-7.

[48] Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H. Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene. 2003 Jul 31;22(31):4851-9.

[49] Kuo PL , Lin CC. Green tea constituent (-)-epigallocatechin-3-gallate inhibits Hep G2 cell proliferation and induces apoptosis through p53-dependent and Fas-mediated pathways. J Biomed Sci. 2003 Mar-Apr;10(2):219-27.

[50]Harvey, S. R. et al. Clin. Exp. Metastasis 6, 431–450 (1988)]

[51] Jankun, J., Keck, R. W., Skrzypczak-Jankun, E. & Swiercz, R. Cancer Res. 57, 559–563 (1997).

[52] Spargon, G. et al. Structure 3, 681–691 (1995).

[53] Yang, C. S. et al. J. Natl Cancer Inst. 85, 1038–1049 (1993).

[54] Jankun, J. , Selman. S.H., Swiercz, R. (1997) Why drinking green tea could prevent cancer. Nature Vol 387 p561

[55] Katiyar,S.K. and Mukhtar,H. (1997) Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols. Carcinogenesis, 18, 1911–1916.[Abstract]

[56] Dong,Z., Huang,C., Brown,R.E. and Ma,W.-Y. (1997) Inhibition of activator protein 1 activity and neoplastic transformation by aspirin. J. Biol. Chem., 272, 9962–9970.[Abstract/ Free Full Text]

[57] Baek SJ, Kim JS, Jackson FR, Eling TE, McEntee MF, Lee SH. Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis. 2004 Dec;25(12):2425-32. Epub 2004 Aug 12.

[58] Naasani,I., Oh-hashi,F., Oh-hara,T., Feng,W.Y., Johnston,J., Chan,K. and Tsuruo,T. (2003) Blocking telomerase by dietary polyphenols is a major mechanism for limiting the growth of human cancer cells in vitro and in vivo. Cancer Res., 63, 824–830.[Abstract/ Free Full Text]

[59] Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993; 85: 1038-49.]

[60] Steele VE, Kelloff GJ, Balentine D, et al. Comparative chemopreventive mechanisms of green tea, black tea and selected polyphenol extracts measured by in vitro bioassays. Carcinogenesis 2000; 21: 63-7.]

[61] Khan SG, Katiyar SK, Agarwal R, Mukhtar H. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hairless mice: possible role in cancer chemoprevention. Cancer Res 1992; 52: 4050-2

[62] Yang C, Chung J, Yang G, et al. Tea and tea polyphenols in cancer prevention. J Nutr 130: 472S-478S, 2000.

[63] Liao S, Umekita Y, Guo J, Kokontis JM, Hiipakka RA. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett. 1995 Sep 25;96(2):239-43.

[64] Tanaka H, Hirose M, Kawabe M, Sano M, Takesada Y, Hagiwara A, Shirai T. Post-initiation inhibitory effects of green tea catechins on 7,12-dimethylbenz[a]anthracene-induced mammary gland carcinogenesis in female Sprague-Dawley rats. Cancer Lett. 1997 Jun 3;116(1):47-52

[65] Hirose M, Mizoguchi Y, Yaono M, Tanaka H, Yamaguchi T, Shirai T. Effects of green tea catechins on the progression or late promotion stage of mammary gland carcinogenesis in female Sprague-Dawley rats pretreated with 7,12-dimethylbenz(a)anthracene.Cancer Lett. 1997 Jan 30;112(2):141-7.

[66] Kavanagh KT, Hafer LJ, Kim DW, Mann KK, Sherr DH, Rogers AE, Sonenshein G . Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture.J Cell Biochem. 2001;82(3):387-98

[67] Sartippour MR, Heber D, Ma J, Lu Q, Go VL, Nguyen M. Green tea and its catechins inhibit breast cancer xenografts.Nutr Cancer. 2001;40(2):149-56.

[68] Yanaga H, Fujii T, Koga T, Araki R, Shirouzu K. Prevention of carcinogenesis of mouse mammary epithelial cells RIII/MG by epigallocatechin gallate. Int J Mol Med. 2002 Sep;10(3):311-5.

[69] Zhou JR, Yu L, Mai Z, Blackburn GL. Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer. 2004 Jan 1;108(1):8-14.

[70]Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993; 85: 1038-49.

[71] McKay DL, Blumberg JF. The role of tea in human health: an update. J Am Coll Nutr 2002; 21: 1-13.

[72] Goldbohm RA, Hertog MG, Brants HA, van Poppel G, van den Brandt PA. Consumption of black tea and cancer risk: a prospective cohort study. J Natl Cancer Inst 1996; 88: 93-100.

[73] Zheng W, Doyle TJ, Kushi LH, Sellers TA, Hong CP, Folsom AR. Tea consumption and cancer incidence in a prospective cohort study of postmenopausal women. Am J Epidemiol 1996; 144: 175-82.

[74] Michels KB, Holmberg L, Bergkvist L, Wolk A. Coffee, tea, and caffeine consumption and breast cancer incidence in a cohort of Swedish women. Ann Epidemiol 2002; 12: 21-6

[75] Tavani A, Pregnolato A, La Vecchia C, Favero A, Franceschi S. Coffee consumption and the risk of breast cancer. Eur J Cancer Prev 1998; 7: 77-82.

[76] Ewertz M. Breast cancer in Denmark. Incidence, risk factors, and characteristics of survival. Acta Oncol 1993; 32: 595-615.

[77] La Vecchia C, Negri E, Franceschi S, D'Avanzo B, Boyle P. Tea consumption and cancer risk. Nutr Cancer 1992; 17: 27-31.

[78] Lubin F, Ron E, Wax Y, Modan B. Coffee and methylxanthines and breast cancer : a case-control study. J Natl Cancer Inst 1985; 74: 569-73.

[79] Rosenberg L, Miller DR, Helmrich SP, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer and the consumption of coffee. Am J Epidemiol 1985; 122: 391-9.

[80] Schairer C, Brinton LA, Hoover RN. Methylxanthines and breast cancer. Int J Cancer 1987; 40: 469-73.

[81] K. Nakachi, K. Suemasu, K. Suga, T. Takeo, K. Imai and Y. Higashi, Influence of drinking green tea on breast cancer malignancy among Japanese patients. Jpn. J. Cancer Res. 89 (1998), pp. 254–261

[82] Bonomi P, Gale M, Von Roenn J, Anderson K, Johnson P, Wolter J, Economou S. Quantitative estrogen and progesterone receptor levels related to progression-free interval in advanced breast cancer patients treated with megestrol acetate or tamoxifen. Semin Oncol. 1988 Apr;15(2 Suppl 1):26-

[83] Inoue M, Tajima K, Mizutani M, Iwata H, Iwase T, Miura S, Hirose K, Hamajima N, Tominaga S. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett 2001; 167: 175-82.

[84] Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. Green tea and risk of breast cancer in Asian Americans. Int J Cancer. 2003 Sep 10;106(4):574-9.

[85] Suzuki Y, Tsubono Y, Nakaya N, Suzuki Y, Koizumi Y, Tsuji I. Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan. Br J Cancer. 2004 Apr 5;90(7):1361-3.

[86] Nagano J, Kono S, Preston DL, Mabuchi K. A prospective study of green tea consumption and cancer incidence, Hiroshima and Nagasaki ( Japan). Cancer Causes Control 2001; 12: 501-8.

[87] Yan YS. Effect of Chinese green tea extracts on the human gastric carcinoma cell in vitro. Zhonghua Yu Fang Yi Xue Za Zhi. 1990 Mar;24(2):80-2.

[87] Wang ZY, Hong JY, Huang MT, Reuhl KR, Conney AH, Yang CS. Inhibition of N-nitrosodiethylamine- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced tumorigenesis in A/J mice by green tea and black tea. Cancer Res. 1992 Apr 1;52(7):1943-7.

[88] Katiyar SK, Agarwal R, Mukhtar H. Protective effects of green tea polyphenols administered by oral intubation against chemical carcinogen-induced forestomach and pulmonary neoplasia in A/J mice. Cancer Lett. 1993 Sep 30;73(2-3):167-72.

[89] Katiyar SK, Agarwal R, Zaim MT, Mukhtar H. Protection against N-nitrosodiethylamine and benzo[a]pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea. Carcinogenesis. 1993 May;14(5):849-55.

[90] Yamane T, Takahashi T, Kuwata K, Oya K, Inagake M, Kitao Y, Suganuma M, Fujiki H. Inhibition of N-methyl-N'-nitro-N-nitrosoguanidine-induced carcinogenesis by (-)-epigallocatechin gallate in the rat glandular stomach.Cancer Res. 1995 May 15;55(10):2081-4.

[91] Yamane T, Nakatani H, Kikuoka N, Matsumoto H, Iwata Y, Kitao Y, Oya K, Takahashi T. Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis. Cancer. 1996 Apr 15;77(8 Suppl):1662-7.

[92] Yan YS. The experiment of tumor-inhibiting effect of green tea extract in animal and human body.Zhonghua Yu Fang Yi Xue Za Zhi. 1993 May;27(3):129-31

[93] Ye W, Yi Y, Luo R. A case-control study on diet and gastric cancer.Zhonghua Yu Fang Yi Xue Za Zhi. 1998 Mar;32(2):100-2.

[94] Yu GP, Hsieh CC, Wang LY, Yu SZ, Li XL, Jin TH. Green-tea consumption and risk of stomach cancer: a population-based case-control study in Shanghai, China. Cancer Causes Control. 1995 Nov;6(6):532-8.

[95] Sasazuki S, Inoue M, Hanaoka T, Yamamoto S, Sobue T, Tsugane S. Green tea consumption and subsequent risk of gastric cancer by subsite: the JPHC Study. Cancer Causes Control. 2004 Jun;15(5):483-91.

[96] Tsubono Y, Nishino Y, Komatsu S, Hsieh CC, Kanemura S, Tsuji I, Nakatsuka H, Fukao A, Satoh H, Hisamichi S. Green tea and the risk of gastric cancer in Japan. N Engl J Med. 2001 Mar 1;344(9):632-6.

[97] Setiawan VW, Zhang ZF, Yu GP, Lu QY, Li YL, Lu ML, Wang MR, Guo CH, Yu SZ, Kurtz RC, Hsieh CC. (2001). Protective effect of green tea on the risks of chronic gastritis and stomach cancer.Int J Cancer, 92: 600-604.

[98] Correa P. Human gastric carcinogenesis: a multistep and multifactorial process - First American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res 1992;52: 6735-40.

[99] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Jiang QW, Yu SZ. Study on the protective effect of green tea on gastric, liver and esophageal cancers

[100] Hoshiyama Y, Kawaguchi T, Miura Y, Mizoue T, Tokui N, Yatsuya H, Sakata K, Kondo T, Kikuchi S, Toyoshima H, Hayakawa N, Tamakoshi A, Ohno Y, Yoshimura T; Japan Collaborative Cohort Study Group. A prospective study of stomach cancer death in relation to green tea consumption in Japan. Br J Cancer. 2002 Jul 29;87(3):309-13

[101] Fujimoto N, Sueoka N, Sueoka E, Okabe S, Suganuma M, Harada M, Fujiki H. Lung cancer prevention with (-)-epigallocatechin gallate using monitoring by heterogeneous nuclear ribonucleoprotein B1. Int J Oncol. 2002 Jun;20(6):1233-9.

[102] Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H Synergistic effects of (--)-epigallocatechin gallate with (--)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9.Cancer Res. 1999 Jan 1;59(1):44-7

[103] Franceschi S, Barra S, La Vecchia C, Bidoli E, Negri E, Talamini R. A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents taxol or adriamycin. Cancer Res. 2000 Feb 15;60(4):901-7

[104] KC Cheng, DS Cahill, H Kasai, S Nishimura and LA Loeb 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G---- T and A----C substitutions Cancer Research, Vol 52, Issue 14 3875-3879,

[105] Shigenaga M. K., Gimeno C. J., Ames B. N. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc. Natl. Acad. Sci. USA, 86: 9697-9701, 1989.

[106] Xu, Y., Ho, C. T., Amin, S. G., Han, C. & Chung, F. L. (1992) Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res. 52:3875-3879

[107] Shi ST, Wang ZY, Smith TJ, Hong JY, Chen WF, Ho CT, Yang CS. Effects of green tea and black tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation, DNA methylation, and lung tumorigenesis in A/J mice. Cancer Res. 1994 Sep 1;54(17):4641-7.

[108] Luo SQ, Liu XZ, Wang CJ. Inhibitory effect of green tea extract on the carcinogenesis induced by asbestos plus benzo(a)pyrene in rat. Biomed Environ Sci. 1995 Mar;8(1):54-8.

[109] Zhu M, Gong Y, Ge G. Effects of green tea on growth inhibition and immune regulation of Lewis lung cancer in mice. Zhonghua Yu Fang Yi Xue Za Zhi. 1997 Nov;31(6):325-9.

[110] Yang CS, Yang GY, Landau JM, Kim S, Liao J. Tea and tea polyphenols inhibit cell hyperproliferation, lung tumorigenesis, and tumor progression. Exp Lung Res. 1998 Jul-Aug;24(4):629-39.

[111] Liu JD, Chen SH, Lin CL, Tsai SH, Liang YC. Inhibition of melanoma growth and metastasis by combination with (-)-epigallocatechin-3-gallate and dacarbazine in mice. J Cell Biochem. 2001;83(4):631-42.

[112] Witschi H. Successful and not so successful chemoprevention of tobacco smoke-induced lung tumors. Exp Lung Res. 2000 Dec;26(8):743-55

[113] Hirose M, Hoshiya T, Mizoguchi Y, Nakamura A, Akagi K, Shirai T. Green tea catechins enhance tumor development in the colon without effects in the lung or thyroid after pretreatment with 1,2-Dimethylhydrazine or 2,2'-dihydroxy-di-n-propylnitrosamine in male F344 rats. Cancer Lett. 2001 Jul 10;168(1):23-9.

[114] Liao J, Yang GY, Park ES, Meng X, Sun Y, Jia D, Seril DN, Yang CS. Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea. Nutr Cancer. 2004;48(1):44-53.

[115] Schuller HM, Porter B, Riechert A, Walker K, Schmoyer R. Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers. Lung Cancer. 2004 Jul;45(1):11-8

[116] Tewes FJ, Koo LC, Meisgen TJ, Rylander R. Tewes FJ, Koo LC, Meisgen TJ, Rylander R. Environ Res. 1990 Jun;52(1):23-33.

[117] PH Kohn Sister chromatid exchange in cancer. Annals of Clinical and Laboratory Science, Vol 13, Issue 4, 267-274

[118] Lee IP, Kim YH, Kang MH, Roberts C, Shim JS, Roh JK. Chemopreventive effect of green tea (Camellia sinensis) against cigarette smoke-induced mutations (SCE) in humans.Cell Biochem Suppl. 1997;27:68-75.

[119] Zhong L, Goldberg MS, Gao YT, Hanley JA, Parent ME, Jin F. A population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China.Epidemiology. 2001 Nov;12(6):695-700

[120] Paschka AG, Butler R, Younf CY. Induction of apoptosis in prostate cancer cell lines by the green tea component, (-)-epigallocatechin-3-gallate. Cancer Lett. 1998; 130: 1-7.

[121] Zhou JR, Yu L, Zhong Y, Blackburn GL. Soy phytochemicals and tea bioactive components synergistically inhibit androgen-sensitive human prostate tumors in mice.J Nutr. 2003 Feb;133(2):516-21

[122] Liao S, Umekita Y, Guo J, Kokontis JM, Hiipakka RA. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett. 1995 Sep 25;96(2):239-43.

[123] Gupta S, Hastak K, Ahmad N, et al. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci USA. 2001; 98: 10350-10355

[124] Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H. Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer.Cancer Res. 2004 Dec 1;64(23):8715 22.

[125] Mooradian A. D., Morley J. E., Korenman S. G. Biological actions of androgens. Endocr. Rev., 8: 1-28, 1987

[126] Mohan R. R., Challa A., Gupta S., Bostwick D. G., Ahmad N., Agarwal R., Marengo S. R., Amini S. B., Paras F., MacLennan G. T., Resnick M. I., Mukhtar H. Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin. Cancer Res., 5: 143-147, 1999

[127] Thompson I. M., Coltman C. A., Brawley O. W., Ryan A. Chemoprevention of prostate cancer. Semin. Urol., 13: 122-129, 1995

[128] Gupta S, Ahmad N, Mohan RR, Husain MM, Mukhtar H. Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase. Cancer Res. 1999 May 1;59(9):2115-20

[129] Katiyar S. K., Agarwal R., Mukhtar H. Protection against malignant conversion of chemically induced benign skin papillomas to squamous cell carcinomas in SENCAR mice by a polyphenolic fraction isolated from green tea. Cancer Res., 53: 5409-5412, 1993.[Abstract]

[130] Agarwal R., Katiyar S. K., Zaidi S. I. A., Mukhtar H. Inhibition of skin tumor promotor-caused induction of epidermal ornithine decarboxylase in SENCAR mice by polyphenolic fraction isolated from green tea and its individual epicatechin derivatives. Cancer Res., 52: 3582-3588, 1992.[Abstract]

[131] Hu G., Han C., Chen J. Inhibition of oncogene expression by green tea and (-)-epigallocatechin gallate in mice. Nutr. Cancer, 24: 203-209, 1995.[Medline]

[132] Yamane T., Takahashi T., Kuwata K., Oya K., Inagakme M., Kitao Y., Suganuma M., Fujiki H. Inhibition of N-methyl-N-nitrosoguanidine-induced carcinogenesis by (-)-epigallocatechin gallate in the rat glandular stomach. Cancer Res., 55: 2081-2084, 1995.[Abstract]

[133] Heilbrun LK, Nomura A, Stemmermann GN. Black tea consumption and cancer risk: a prospective study. Br J Cancer. 1986; 54: 677-683

[134] Jain MG, Hislop GT, Howe GR, Burch JD, Ghadirian P. Alcohol and other beverage use and prostate cancer risk among Canadian men. Int J Cancer. 1998 Dec 9;78(6):707-11.

[135] Ellison LF. Tea and other beverage consumption and prostate cancer risk: a Canadian retrospective cohort study.Eur J Cancer Prev. 2000 Apr;9(2):125-30

[136] Jian L, Xie LP, Lee AH, Binns CW. Protective effect of green tea against prostate cancer: a case-control study in southeast China. Int J Cancer. 2004 Jan 1;108(1):130-5

[137] Fleshner N. Defining high-risk prostate cancer: current status.Can J Urol. 2005 Feb;12(1 Supp 1):14-7

[138] Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P, Tan W, Fitch TR, Rowland KM, Young CY, Flynn PJ. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma.Cancer. 2003 Mar 15;97(6):1442-6.

[139] Chen J. The effects of Chinese tea on the occurrence of esophageal tumors induced by N-nitrosomethylbenzylamine in rats.Prev Med. 1992 May;21(3):385-91

[140] Wang ZY, Wang LD, Lee MJ, Ho CT, Huang MT, Conney AH, Yang CS. Inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by green and black tea.Carcinogenesis. 1995 Sep;16(9):2143-8.

[141] Wang C, Wang X, Li Y, Jiang Y, Deng S, Zhao M. A preliminary study of the preventive and blocking effect of green tea grown in mengding mountain area on the esophageal cancer in rats.Hua Xi Yi Ke Da Xue Xue Bao. 1996 Jun;27(2):206-8.

[142] Morse MA, Kresty LA, Steele VE, Kelloff GJ, Boone CW, Balentine DA, Harbowy ME, Stoner GD. Effects of theaflavins on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis. Nutr Cancer. 1997;29(1):7-12.

[143] de Boer JG, Yang H, Holcroft J, Skov K. Chemoprotection against N-nitrosomethylbenzylamine-induced mutation in the rat esophagus.Nutr Cancer. 2004;50(2):168-73.

[144] Gao YT, McLaughlin JK, Blot WJ, Ji BT, Dai Q, Fraumeni JF Jr. Reduced risk of esophageal cancer associated with green tea consumption . J Natl Cancer Inst. 1994 Jun 1;86(11):855-8.

[145] Wang LD, Zhou Q, Feng CW, Liu B, Qi YJ, Zhang YR, Gao SS, Fan ZM, Zhou Y, Yang CS, Wei JP, Zheng S. Intervention and follow-up on human esophageal precancerous lesions in Henan, northern China, a high-incidence area for esophageal cancer.Gan To Kagaku Ryoho. 2002 Feb;29 Suppl 1:159-72.

[146] Yang CS, Lee MJ, Chen L. Human salivary tea catechin levels and catechin esterase activities: implication in human cancer prevention studies.Cancer Epidemiol Biomarkers Prev. 1999 Jan;8(1):83-9.

[147] Wang M, Guo C, Li M. A case-control study on the dietary risk factors of upper digestive tract cancer. Zhonghua Liu Xing Bing Xue Za Zhi. 1999 Apr;20(2):95-7.

[148] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Chen CW, Wei GR, Zhou XM, Jiang QW, Yu SZ. A case-control study on drinking green tea and decreasing risk of cancers in the alimentary canal among cigarette smokers and alcohol drinkers. Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Mar;24(3):192-5.

[149] Kinjo Y, Cui Y, Akiba S, Watanabe S, Yamaguchi N, Sobue T, Mizuno S, Beral V. Mortality risks of oesophageal cancer associated with hot tea, alcohol, tobacco and diet in Japan. J Epidemiol. 1998 Oct;8(4):235-43.

[150] Gao Y, McLaughlin JK, Gridley G, et al: Risk factors for esophageal cancer in Shanghai, China: II. Role of diet and nutrients. Int J Cancer 58:197-202, 1994

[151] Castellsague et al., 2000 X. Castellsague, N. Munoz, E. De Stefani, C.G. Victora, R. Castelletto and P.A. Rolon, Influence of mate drinking, hot beverages and diet on esophageal cancer risk in South America, Int. J. Cancer 88 (2000), pp. 658–664

[152] Nihal M, Ahmad N, Mukhtar H, Wood GS. Anti-proliferative and proapoptotic effects of (-)-epigallocatechin-3-gallate on human melanoma: Possible implications for the chemoprevention of melanoma. Int J Cancer. 2004 Dec 17

[153] Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC. Dual mechanisms of green tea extract (EGCG)-induced cell survival in human epidermal keratinocytes. FASEB J. 2003 Oct;17(13):1913-5. Epub 2003 Aug 01.

[154] An KP, Athar M, Tang X, Katiyar SK, Russo J, Beech J, Aszterbaum M, Kopelovich L, Epstein EH Jr, Mukhtar H, Bickers DR. Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches . Photochem Photobiol. 2002 Jul;76(1):73-80.

[155] Katiyar SK , Bergamo BM, Vyalil PK , Elmets CA. Green tea polyphenols: DNA photodamage and photoimmunology . J Photochem Photobiol B. 2001 Dec 31;65(2-3):109-14.

[156] Katiyar SK , Perez A, Mukhtar H. Green tea polyphenol treatment to human skin prevents formation of ultraviolet light B-induced pyrimidine dimers in DNA . Clin Cancer Res. 2000 Oct;6(10):3864-9.

[157] Wang ZY, Agarwal R, Bickers DR, Mukhtar H. Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols. Carcinogenesis. 1991 Aug;12(8):1527-30

[158] Wang ZY, Huang MT, Ferraro T, Wong CQ, Lou YR, Reuhl K, Iatropoulos M, Yang CS, Conney AH. Inhibitory effect of green tea in the drinking water on tumorigenesis by ultraviolet light and 12-O-tetradecanoylphorbol-13-acetate in the skin of SKH-1 mice . Cancer Res. 1992 Mar 1;52(5):1162-70.

[159] Katiyar SK, Agarwal R, Mukhtar H. Inhibition of both stage I and stage II skin tumor promotion in SENCAR mice by a polyphenolic fraction isolated from green tea: inhibition depends on the duration of polyphenol treatment . Carcinogenesis. 1993 Dec;14(12):2641-3.

[160] Wang ZY, Huang MT, Lou YR, Xie JG, Reuhl KR, Newmark HL, Ho CT, Yang CS, Conney AH. Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice . Cancer Res. 1994 Jul 1;54(13):3428-35.

[161] Gensler HL, Timmermann BN, Valcic S, Wachter GA, Dorr R, Dvorakova K, Alberts DS. Prevention of photocarcinogenesis by topical administration of pure epigallocatechin gallate isolated from green tea . Nutr Cancer. 1996;26(3):325-35.

[162] Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, Hard GC, Conney AH. Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea . Cancer Res. 1997 Jul 1;57(13):2623-9.

[163] Katiyar SK, Mohan RR, Agarwal R, Mukhtar H. Protection against induction of mouse skin papillomas with low and high risk of conversion to malignancy by green tea polyphenols . Carcinogenesis. 1997 Mar;18(3):497-502.

[164] Record IR, Dreosti IE. Protection by tea against UV-A + B-induced skin cancers in hairless mice . Nutr Cancer. 1998;32(2):71-5.

[165] Higashi-Okai K, Okai Y. Potent suppressive activity of chlorophyll a and b from green tea (Camellia sinensis) against tumor promotion in mouse skin . J UOEH. 1998 Sep 1;20(3):181-8.

[166] Higashi-Okai K, Otani S, Okai Y. Potent suppressive activity of pheophytin a and b from the non-polyphenolic fraction of green tea (Camellia sinensis) against tumor promotion in mouse skin. Cancer Lett. 1998 Jul 17;129(2):223-8.

[167] Lu YP, Lou YR, Lin Y, Shih WJ, Huang MT, Yang CS, Conney AH. Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat . Cancer Res. 2001 Jul 1;61(13):5002-9.

[168] Zheng W, Doyle TJ, Kushi LH, Sellers TA, Hong CP, Folsom AR. Tea consumption and cancer incidence in a prospective cohort study of postmenopausal women . Am J Epidemiol. 1996 Jul 15;144(2):175-82.