Description and Constituents

Tea is one of the most widely consumed beverages in the world today, second only to water, and its medicinal properties have been widely explored. The tea plant, Camellia sinensis, is a member of the Theaceae family, and black, oolong, and green tea are produced from its leaves. It is an evergreen shrub or tree and can grow to heights of 30 feet, but is usually pruned to 2-5 feet for cultivation. The leaves are dark green, alternate and oval, with serrated edges, and the blossoms are white, fragrant, and appear in clusters or singly. Unlike black and oolong tea, green tea production does not involve oxidation of young tea leaves. Green tea is produced from steaming fresh leaves at high temperatures, thereby inactivating the oxidizing enzymes and leaving the polyphenol content intact. The polyphenols found in tea are more commonly known as flavanols or catechins and comprise 30-40 percent of the extractable solids of dried green tea leaves. The main catechins in green tea are epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate (EGCG), with the latter being the highest in concentration. Green tea polyphenols have demonstrated significant antioxidant, anticarcinogenic, anti-inflammatory, thermogenic, probiotic, and antimicrobial properties in numerous human, animal, and in vitro studies.1,2

Mechanisms of Action

The anticarcinogenic properties of green tea polyphenols, mainly EGCG, are likely a result of inhibition of biochemical markers of tumor initiation and promotion, induction of apoptosis, and inhibition of cell replication rates, thus retarding the growth and development of neoplasms.3,4 Their antioxidant potential is directly related to the combination of aromatic rings and hydroxyl groups that make up their structure, and is a result of binding and neutralization of free radicals by the hydroxyl groups. In addition, green tea polyphenols stimulate the activity of hepatic detoxification enzymes, thereby promoting detoxification of xenobiotic compounds, and are also capable of chelating metal ions, such as iron, that can generate radical oxygen species.5,6

Green tea polyphenols inhibit the production of arachidonic acid metabolites such as pro-inflammatory prostaglandins and leukotrienes, resulting in a decreased inflammatory response. Human and animal studies have demonstrated EGCG's ability to block inflammatory responses to ultraviolet A and B radiation as well as significantly inhibiting the neutrophil migration that occurs during the inflammatory process.7-9

Research on green tea's thermogenic properties indicates a synergistic interaction between its caffeine content and catechin polyphenols may result in prolonged stimulation of thermogenesis. Studies have also shown green tea extracts are capable of reducing fat digestion by inhibiting digestive enzymes.10,11 Although the exact mechanism is unknown, green tea catechins have been shown to significantly raise levels of Lactobacilli and Bifidobacteria while decreasing levels of numerous potential pathogens.12 Studies have also demonstrated green tea's antibacterial properties against a variety of gram-positive and gram-negative species.13

Clinical Indications

Cancer Prevention/Inhibition:
Several studies have demonstrated green tea polyphenols' preventative and inhibitory effects against tumor formation and growth. While the studies are not conclusive, green tea polyphenols, particularly EGCG, may be effective in preventing cancer of the prostate, breast, esophagus, stomach, pancreas, and colon.14 There is also some evidence that green tea polyphenols may be chemopreventative or inhibitory toward lung, skin, and liver cancer,15-17 bladder and ovarian tumors,18,19 leukemia,20 and oral leukoplakia.21

Antioxidant Applications:
Many chronic disease states and inflammatory conditions are a result of oxidative stress and subsequent generation of free radicals. Some of these include heart disease (resulting from LDL oxidation), renal disease and failure, several types of cancer, skin exposure damage caused by ultraviolet (A and B) rays, as well as diseases associated with aging. Green tea polyphenols are potent free radical scavengers due to the hydroxyl groups in their chemical structure. The hydroxyl groups can form complexes with free radicals and neutralize them, preventing the progression of the disease process.22

Obesity/Weight Control:
Recent studies on green tea's thermogenic properties have demonstrated a synergistic interaction between caffeine and catechin polyphenols that appears to prolong sympathetic stimulation of thermogenesis. A human study of green tea extract containing 90 mg EGCG taken three times daily concluded that men taking the extract burned 266 more calories per day than did those in the placebo group and that green tea extract's thermogenic effects may play a role in controlling obesity.23 Green tea polyphenols have also been shown to markedly inhibit digestive lipases in vitro, resulting in decreased lipolysis of triglycerides, which may translate to reduced fat digestion in humans.10,11

Intestinal Dysbiosis and Infection:
A small study in Japan demonstrated a special green tea catechin preparation (30.5% EGCG) was able to positively affect intestinal dysbiosis in nursing home patients by raising levels of Lactobacilli and Bifidobacteria while lowering levels of Enterobacteriaceae, Bacteroidaceae, and eubacteria. Levels of pathogenic bacterial metabolites were also decreased.12 An in vitro study also demonstrated green tea's antimicrobial activity against a variety of gram-positive and gram-negative pathogenic bacteria that cause cystitis, pyelonephritis, diarrhea, dental caries,24 pneumonia, and skin infections.13

Other Applications:
Sickle cell anemia is characterized by a population of "dense cells" that may trigger vaso-occlusion and the painful sickle cell "crisis." One study demonstrated that 0.13 mg/mL green tea extract was capable of inhibiting dense-cell formation by 50 percent.25 Another potential therapeutic application of green tea is the treatment of psoriasis. The combination therapy of psoralens and ultraviolet A radiation is highly effective but has unfortunately been shown to substantially increase the risk for developing squamous cell carcinoma and melanoma. An in vitro study using human and mouse skin demonstrated that pre- and post-treatment with green tea extract inhibited DNA damage induced by the psoralen/ultraviolet A radiation exposure.8

Dosage and Toxicity

Green tea is generally considered a safe, non-toxic beverage and consumption is usually without side-effects. The average cup of green tea, however, contains from 10-50 mg of caffeine and overconsumption may cause irritability, insomnia, nervousness, and tachycardia. Because studies on its possible teratogenic effect are inconclusive, caffeine consumption is contraindicated during pregnancy. Lactating women should also limit caffeine intake to avoid sleep disorders in infants.26

The dosage for green tea beverage varies, depending on the clinical situation and desired therapeutic effect. The phenolic content of green tea infusion is between 50-100 mg polyphenols per cup, depending on species, harvesting variables, and brewing methods,27 with typical dosages ranging from 3 to 10 cups per day. Cancer preventative effects are usually associated with dosages in the higher end of the range.28 Green tea extracts standardized to 80-percent total polyphenols are dosed at an average of 500-1500 mg per day.

References

1. Alschuler L. Grean Tea: Healing tonic. Am J Natur Med 1998;5:28-31.
   
   
2. Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992;21:334-350.
   
   
3. Nihal A, Hasan M. Green tea polyphenols and cancer: biological mechanisms and practical implications. Nutr Rev 1999;57:78-83.
   
   
4. Ahmad N, Feyes DK, Nieminen AL, et al. Green tea constituent epigallacatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881-1886.
   
   
5. Serafini M, Ghiselli A, Ferro-Luzzi A. In vivo antioxidant effect of green and black tea in man. Eur J Clin Nutr 1996;50:28-32.
   
   
6. Erba D, Riso P, Colombo A, Testolin G. Supplementation of Jurkat T cells with green tea extract decreases oxidative damage due to iron treatment. J Nutr 1999;129:2130-2134.
   
   
7. Katiyar SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin. Photochem Photobiol 1999;69:148-153.
   
   
8. Zhao JF, Zhang YJ, Jin XH, et al. Green tea protects against psoralen plus ultraviolet A-induced photochemical damage to skin. J Invest Dermatol 1999;113:1070-1075.
   
   
9. Hofbauer R, Frass M, Gmeiner B, et al. The green tea extract epigallocatechin gallate is able to reduce neutrophil transmigration through monolayers of endothelial cells. Wien Klin Wochenschr 1999;111:276-282.
   
   
10. Dulloo AG, Seydoux J, Girardier L, et al. Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine, and sympathetic activity. Int J Obes Relat Metab Disord 2000;24:252-258.

American Journal of Clinical Nutrition
Vol. 71, No. 6, 1698S-1702s, June 2000

ABSTRACT

The tea plant Camellia sinesis is cultivated in 30 countries. Epidemiologic observations and laboratory studies have indicated that polyphenolic compounds present in tea may reduce the risk of a variety of illnesses, including cancer and coronary heart disease. Most studies involved green tea, however; only a few evaluated black tea.

Results from studies in rats, mice, and hamsters showed that tea consumption protects against lung, forestomach, esophagus, duodenum, pancreas, liver, breast, colon, and skin cancers induced by chemical carcinogens. Other studies showed the preventive effect of green tea consumption against atherosclerosis and coronary heart disease, high blood cholesterol concentrations, and high blood pressure.

Because the epidemiologic studies and research findings in laboratory animals have shown the chemopreventive potential of tea polyphenols in cancer, the usefulness of tea polyphenols for humans should be evaluated in clinical trials. One such phase 1 clinical trial is currently under way at the MD Anderson Cancer Center in collaboration with Memorial Sloan-Kettering Cancer Center. This study will examine the safety and possible efficacy of consuming the equivalent of >10 cups (>2.4 L) of green tea per day.

The usefulness of tea polyphenols may be extended by combining them with other consumer products such as food items and vitamin supplements. This "designer-item" approach may be useful for human populations, but it requires further study.

INTRODUCTION

Significant progress has been made in understanding diseases that cause alarming mortality and morbidity in humans: their processes, possible prevention, and therapies. Cancer and coronary heart disease are the most important of these disorders. Because of research efforts over the past 30 y, it is now well appreciated that although the causes of the major diseases are diverse and countless, changes in dietary habits and lifestyles may reduce their risk in many cases. Research has indicated that many common foods have nonnutritive components, commonly known as chemopreventive agents that may provide protection against a variety of illnesses, including cancer and coronary heart disease. One such class of agents is antioxidants. The predominant mechanism of protective action of antioxidants appears to be the destruction of free radicals.

The water extract of the dry leaves of the plant Camellia sinesis, an evergreen shrub of the Theaceae family, is a popular beverage commonly known as tea. A drink that contains many compounds, including a mixture of polyphenols, tea has been consumed by some human populations for many generations and, in some parts of the world, has been considered to have health-promoting potential (1). Extensive laboratory research and the epidemiologic findings of the past 20 y have shown that polyphenolic compounds present in tea may reduce the risk of a variety of illnesses.

CONSUMPTION, COMPOSITION, AND CHEMISTRY OF TEA

The tea plant C. sinensis is native to Southeast Asia but is currently cultivated in >30 countries around the world. Tea is consumed worldwide, although in greatly different amounts; it is generally accepted that, next to water, tea is the most consumed beverage in the world, with per capita consumption of approximately 120 mL/d (2). Of the total amount of tea produced and consumed in the world, 78% is black, 20% is green, and <2% is oolong tea. Black tea is consumed primarily in Western countries and in some Asian countries, whereas green tea is consumed primarily in China, Japan, India, and a few countries in North Africa and the Middle East. Oolong tea production and consumption are confined to southeastern China and Taiwan (2).

Green, black, and oolong teas undergo different manufacturing processes. To produce green tea, freshly harvested leaves are rapidly steamed or pan-fried to inactivate enzymes, thereby preventing fermentation and producing a dry, stable product. Epicatechins are the main compounds in green tea, accounting for its characteristic color and flavor.

For the production of black and oolong teas, the fresh leaves are allowed to wither until their moisture content is reduced to approximately 55% of the original leaf weight, which results in the concentration of polyphenols in the leaves. The withered leaves are then rolled and crushed, initiating fermentation of the polyphenols. During these processes, the catechins are converted to theaflavins and thearubigins. Oolong tea is prepared by firing the leaves shortly after rolling to terminate the oxidation and dry the leaves. Normal oolong tea is considered to be about half as fermented as black tea. The fermentation process results in oxidation of simple polyphenols to more complex condensed polyphenols to give black and oolong teas their characteristic colors and flavors.

The composition of the tea leaves depends on a variety of factors, including climate, season, horticultural practices, and the type and age of the plant. The chemical composition of green tea is similar to that of the leaf. Green tea contains polyphenolic compounds, which include flavanols, flavandiols, flavonoids, and phenolic acids and account for30% of the dry weight of green tea leaves. Most of the polyphenols in green tea are flavanols, commonly known as catechins; the major catechins in green tea are (-)-epicatechin, (-)-epicatechin-3-gallate, (-)-epigallocatechin, and (-)-epigallocatechin-3-gallate (EGCG). In black teas, the major polyphenols are theaflavin and thearubigin.

TEA POLYPHENOLS AND THE RISK OF CANCER

Abundant experimental and epidemiologic evidence accumulated mainly in the past decade from several centers worldwide provides a convincing argument that polyphenolic antioxidants present in green and black tea can reduce cancer risk in a variety of animal tumor bioassay systems (2–4). Most of the studies showing the preventive effects of tea were conducted with green tea; only a few studies assessed the usefulness of black tea (2). These studies showed that the consumption of tea and its polyphenolic constituents affords protection against chemical carcinogen– or ultraviolet radiation–induced skin cancer in the mouse model.

Tea consumption also affords protection against cancers induced by chemical carcinogens that involve the lung, forestomach, esophagus, duodenum, pancreas, liver, breast, colon, and skin in mice, rats, and hamsters. We reviewed this area of research (2), and the bioavailability of the polyphenols from tea has been established by others (5). The relevance of the extensive laboratory information for human health can be assessed only through epidemiologic observations, however, especially in a population with high cancer risk.

Much of the cancer-preventive effects of green tea are mediated by EGCG , the major polyphenolic constituent of green tea (2). One cup (240 mL) of brewed green tea contains up to 200 mg EGCG. Many consumer products, including shampoos, creams, drinks, cosmetics, lollipops, and ice creams, have been supplemented with green tea extracts and are available in grocery stores and pharmacies.

The use of biochemical modulators in cancer chemotherapy has been studied extensively (6). The adverse effects of modulating drugs can be life threatening, and their use increases the patient's medication burden as well. Thus, the substances used in diet and beverages should be studied for their potential as biochemical modulators that could increase the efficacy of therapy. In this regard, Sadzuka et al (6) showed that the oral administration of green tea enhanced the tumor-inhibitory effects of doxorubicin on Ehrlich ascites carcinomas implanted in CDF1 and BDF1 mice. The study showed that green tea treatment increases the concentration of doxorubicin in tumor but not in normal tissue. If these observations can be verified in human populations, they may have relevance to cancer chemotherapy.

TEA POLYPHENOLS AND THE RISK OF CORONARY HEART DISEASE

Coronary heart disease is most prevalent in the Western world, probably as a result of the lifestyle in this part of the world, which includes a diet high in saturated fats and low physical activity, and the large proportion of the population who smoke cigarettes and have high blood pressure. A variety of epidemiologic studies showed the preventive effect of green tea consumption against atherosclerosis and coronary heart disease (see references 1 and 7 and the references therein). Tea consumption has also been shown to reduce the risk of high blood cholesterol concentrations and high blood pressure (8). In addition, studies in experimental animals showed the preventive effect of green tea against atherosclerosis (9).

EFFECTS OF TEA POLYPHENOLS AGAINST OTHER DISEASES

Many studies have shown that the consumption of tea or its polyphenols can afford protection against diseases other than cancer and coronary heart disease. A few of these studies are as follows: Weisburger (10) showed that tea is protective against stroke; Fujita (11) and Kao and P’eng (12) reported that tea consumption lowers the risk of osteoporosis; Imai and Nakachi (13) reported protection against liver disease; Horiba et al (14), Terada et al (15), and Young et al (16) reported that tea consumption provides protection against bacterial infection; and Nakayama et al (17) and Tao (18) found that tea provides protection against viral infection.

ANTI-INFLAMMATORY EFFECTS OF TEA

In several studies from our laboratory and elsewhere, the polyphenolic fraction from green tea was shown to protect against inflammation caused by certain chemicals, such as 12-O-tetradecanoylphorbol-13-acetate, a principal irritant in croton oil (2, 19, 20), or by ultraviolet radiation B (290–320 nm) (21). Green tea has also been shown to be effective against the immunosuppression caused by ultraviolet radiation-B (2, 22). In addition, green tea polyphenols have shown protection against cytokines induced by tumors (23).

MECHANISMS OF BIOLOGICAL EFFECTS OF TEA

Because tea consumption has been shown to have protective effects against a variety of diseases, defining the mechanisms of the biological effects of tea is important. In addition, elucidation of mechanisms may provide additional opportunities to intervene at other targets. Initial mechanistic studies (reviewed in reference 2) regarding the cancer chemopreventive effects of green tea or its polyphenols largely focused on:

1) protection against mutagenicity and genotoxicity

2) inhibition of biochemical markers of tumor initiation,

3) inhibition of biochemical markers of tumor promotion,

4) effects on detoxification enzymes,

5) trapping of activated metabolites of carcinogens, and

6) antioxidant and free radical scavenging activity. Novel mechanistic work to define the anticarcinogenic effects of polyphenolic extracts from green tea and its constituents has been pursued; recent advances in this area are described in the following sections.

Green tea activates mitogen-activated protein kinases

The activation of mitogen-activated protein kinases by green tea polyphenols was shown to be a potential signaling pathway in the regulation of phase II enzyme gene expression mediated by an antioxidant-responsive element (24). In this study, green tea polyphenols induced chloramphenicol acetyltransferase (CAT) activity in human hepatoma HepG2 cells transfected with a plasmid construct containing an antioxidant-responsive element and a minimal glutathione S-transferase Ya promoter linked to the CAT reporter gene. This result indicates that green tea polyphenols stimulate the transcription of phase II detoxifying enzymes through the antioxidant-responsive element. In addition, green tea polyphenol treatment of HepG2 cells resulted in a significant activation of extracellular signal–regulated kinase 2 and c-Jun N-terminal kinase 1, which are members of the mitogen-activated protein kinase family. Green tea polyphenol treatment also increased messenger RNA amounts of the immediate-early genes c-jun and c-fos.

EGCG inhibits urokinase activity

A widely publicized study showed that the anticancer activity of EGCG in green tea might be due to inhibition of the enzyme urokinase (u-plasminogen activator), one of the most frequently expressed enzymes in human cancers (25). With the use of molecular modeling, the authors showed that EGCG binds to urokinase, blocking His 57 and Ser 195 of the urokinase catalytic triad and extending toward Arg 35 from a positively charged loop of urokinase. This computer-based calculation was verified by quantifying the inhibition of urokinase activity with a spectrophotometric amidolytic assay. The validity of this finding has been challenged, however (26).

Green tea induces apoptosis and cell cycle arrest

In recent years, apoptosis has become a challenging area of biomedical research. The life spans of both normal and cancer cells within living systems are thought to be significantly affected by the rate of apoptosis, a programmed type of cell death that differs from necrotic cell death and is regarded as a normal process of cell elimination (27). It follows that the chemopreventive agents that can modulate apoptosis and thereby affect the steady state cell population may be useful in the management and therapy of cancer.

Many cancer-chemopreventive agents induce apoptosis and, conversely, several tumor promoters inhibit apoptosis (28–30). It is reasonable, therefore, to assume that chemopreventive agents that have proven effects in animal tumor bioassay systems or human epidemiologic studies on the one hand and that induce apoptosis of cancer cells on the other hand may have wider implications for the management of cancer. Only a few chemopreventive agents are known to cause apoptosis, however (31).

We found that EGCG induced apoptosis and cell cycle arrest in human epidermoid carcinoma cells A431 (32). Importantly, we also found that the apoptotic response of EGCG was specific to cancer cells, because the induction of apoptosis was also observed in human carcinoma keratinocytes HaCaT, human prostate carcinoma cells DU145, and mouse lymphoma cells LY-R but not in normal human epidermal keratinocytes.

EGCG suppresses extracellular signals and cell proliferation through epidermal growth factor receptor binding

Liang et al (33) showed that EGCG could significantly inhibit DNA synthesis in A431 cells. In addition, EGCG inhibited the protein tyrosine kinase activities of epidermal growth factor (EGF) receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor but not of pp60v-src, protein kinase C, and protein kinase A. EGCG also inhibited the phosphorylation of EGF receptor by EGF and blocked the binding of EGF to its receptor. These findings suggest that EGCG might inhibit the process of tumor formation by blocking cellular signal transduction pathways.

EGCG blocks induction of nitric oxide synthase by down-regulating transcription factor nuclear factor B

Lin and Lin (34) assessed the effects of EGCG on nitric oxide production by murine peritoneal macrophages. Their results suggest that EGCG blocked early events of nitric oxide synthase induction by inhibiting the binding of transcription factor nuclear factor B to the inducible nitric oxide synthase (iNOS) promoter, thereby inhibiting the induction of iNOS transcription.

EGCG and theaflavins inhibit tumor promoter-induced activator protein 1 activation and cell transformation

To examine antitumor promotion effects of EGCG and theaflavins at the molecular level, Dong et al (35) used a JB6 mouse epidermal cell line, a system that has been used extensively as an in vitro model for tumor promotion studies. EGCG and theaflavins inhibited EGF- or 12-O-tetradecanoyl-phorbol-13-acetate–induced cell transformation in a dose-dependent manner. EGCG and theaflavins also inhibited activator protein 1 (AP-1)-dependent transcriptional activity and DNA binding activity. Finally, this study showed that the inhibition of AP-1 activation occurs through the inhibition of a pathway dependent on c-Jun N-terminal kinase.

TEA AND CLINICAL TRIALS

Because epidemiologic studies and research findings in laboratory animals have shown the chemopreventive potential of tea polyphenols in cancer, the usefulness of these polyphenols for humans should be evaluated in clinical trials. The first such trial is being conducted by the MD Anderson Cancer Center in collaboration with the Memorial Sloan-Kettering Cancer Center; MD Anderson has obtained an Investigational New Drug application permit from the US Food and Drug Administration to begin phase 1 clinical trials. To examine the safety and possible efficacy of consuming the equivalent of >10 cups (>2.4 L) of green tea/d, 30 cancer patients with advanced solid tumors will be given daily green tea for >6 months.

CONCLUSION AND FUTURE DIRECTIONS

Dietary habits influence the risk of developing a variety of diseases, especially cancer and heart disease. The use of dietary substances is receiving increasing attention as a practical approach for reducing the risk of developing these diseases. Epidemiologic observations and laboratory studies have indicated that tea consumption may have beneficial effects in reducing certain types of cancer in some populations. Although a considerable body of information provides evidence supporting the preventive potential of tea against cancer, a proper understanding of the mechanisms by which tea polyphenols reduce the risk of diseases is necessary to devise strategies for better health. Black tea is the major form of tea consumed, but its chemistry, biological activities, and chemopreventive properties, especially of the polyphenols that are present, are not well defined.

Because information on the bioavailability of tea polyphenols after tea consumption is limited in humans, studies on absorption, distribution, and metabolism of green and black tea polyphenols in animals and humans are needed. After careful evaluation of the available data and additional studies, specific recommendations may be made for consumption of tea by humans. The usefulness of tea polyphenols may be extended by combining them with other consumer products, such as food items and vitamin supplements. This "designer-item" approach may be useful for the human population.

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Green tea, a popular beverage consumed worldwide, has been shown to possess cancer chemopreventive effects in a wide range of target organs in rodent carcinogenesis models. The chemopreventive effects of green tea against tumorigenesis and tumor growth have been attributed to the biochemical and pharmacological activities of its polyphenolic constituents. Epidemiological studies, although inconclusive, suggest a protective effect of tea consumption on some cancer types in humans. Limited epidemiological studies indicate that people who consume tea regularly may have a lower risk of cancer of the prostate (CaP). Further, the Japanese and Chinese populations who regularly consume tea, especially green tea, have one of the lowest incidences of CaP in the world. In addition, the incidence of CaP is also low in other Asian men, who consume a traditional low-fat diet and tea.

Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits prostate cancer development and increases survival in these mice.

In two separate experiments, the cumulative incidence of palpable tumors in untreated mice was 100%. In these 95%, 65%, 40%), and 25% exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, green tea polyphenols (GTP) resulted in (i) significant delay in primary tumor incidence and tumor burden, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate.

The striking observation of this study was that green tea polyphenol (GTP) infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of prostate cancer (CaP) cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.

In the present study, we determined the consequence of oral infusion of a polyphenolic fraction from green tea (GTP) on prostate cancer (CaP) development and progression at a human-achievable dose. Results demonstrate that oral infusion of GTP causes a significant inhibition in the development, progression, and metastasis of CaP to distant organ sites. GTP was found to result in significant prevention or delay (44% inhibition) in prostate cancer development. GTP did not exhibit any symptoms of toxicity or apparent signs of ill health. GTP infusion resulted in complete absence of hyperplasia in the genitourinary (GU) apparatus, especially in the seminal vesicles.

Because green tea is known to induce selective apoptosis in cancer cells, we hypothesized that the observed inhibition of prostate tumorigenesis by GTP infusion is mediated by increased apoptosis of cancerous cells. To test our hypothesis, we used multiple approaches of apoptosis determination. A significant increase in apoptotic index (2.12 6 0.1 vs. 27.7 6 3.2% control vs. GTP) was observed.

Extended tumor-free survival and survival probability is the most desirable effect of any chemo-prevention regimen. Therefore, in the next series of experiments, we evaluated whether or not green tea polyphenol (GTP) infusion leads to tumor-free survival and prolongs life expectancy. Our data indicated that GTP resulted in the prolongation of lifespan and significantly increased the tumor-free survival inasmuch as 50% remain tumor-free. In addition, GTP exhibited a significant increase (70% higher) in life expectancy.

Because prostate cancer is typically diagnosed in men aged 50 years and older, even a slight delay in the onset and subsequent progression of the disease through the use of chemopreventive agent(s) could have important health benefits. The most notable implication of our work is that oral infusion of a human-achievable dose of green tea results in significant inhibition in development and progression of prostate cancer along with increased survival in an animal model that emulates human disease. These data, therefore, suggest that green tea consumption may have inhibitory effects on prostate carcinogenesis in humans.

A number of studies have shown the growth-inhibitory effects of green tea against many animal tumor bioassay systems (Katiyar S, et al, Cancer Res, 52, 6890–6897, 1992), (Katiyar S, et al, Carcinogenesis, 14, 849–855, 1993), (Lu Y, et al, Carcinogenesis, 18, 2163–2169, 1997), (Landau J, et al, Carcinogenesis 19, 501–507, 1998). Recent laboratory studies have indicated that green tea and its polyphenolic constituents impart inhibitory effects on the activities of many enzymatic, metabolic, and signaling pathways that have relevance to cancer development and progression (Liao S & Hiipakka R, Biochem Biophys Res Commun, 214, 833–838, 1995), (Jankun J, et al., Nature, 387, 561, 1997), (Cao Y, & Cao R, Nature, 398, 381, 1999), (Garbisa S,et al, Nat. Med, 5, 1216, 1999), (Nam S, et al, J Biol Chem, 276, 13322–13330, 2001), (Menegazzi M, et al, FASEB J, 15, 1309–1311, 2001).

Studies have shown that polyphenols present in green tea and caffeine possess cancer chemopreventive effects (Huang M, et al, Cancer Res, 57, 2623–2629, 1997). Epidemiological studies suggest a protective role of green tea against prostate cancer development (Heilbrun L, et al, Br J Cancer 54, 677–683, 1986); (Kinlen L, et al, Br J Cancer 58, 397–401, 1988); (Katiyar S, Mukhtar H, Int J Oncol, 8, 221–238, 1996); (Kohlmeier L, et al, Nutr Cancer 27, 1–13, 1997); (Bushman J, Nutr Cancer, 31, 151–159, 1998). Cell culture studies have shown that GTP inhibits growth of several types of human CaP cells (Ahmad N, et al, J Natl Cancer Inst, 89, 1881–1886, 1997); (Yang G, et al, Carcinogenesis 19, 611–616, 1998); (Valcic S, et al, Anticancer Drugs 7, 461–468, 1996); (Ahmad N, et al, J Natl Cancer Inst, 89, 1881–1886, 1997); (Paschka A, et al, Cancer Lett 130, 1–7, 1998); (Gupta S, et al, Toxicol Appl Pharmacol, 164, 82–90, 2000)

Studies indicate that 23% of prostate cancer patients receiving surgical intervention still show evidence of disease progression (Satariano W, Cancer 83, 1180–1188. (52), (1998). Once the disease becomes hormone refractory, treatment is palliative and median lifespan is less than 12 months. Therefore, agents that may prolong the survival and quality of life of such patients could have immediate clinical importance. Studies from our laboratory have shown that green tea polyphenols show promising testosterone-mediated cell growth inhibitory effects in vitro as well as in vivo (Gupta S, et al, Cancer Res. 59, 2115–2120, 1999). In the present study, GTP infusion resulted in a significant increase in tumor-free survival and survival probability. Based on these results, we suggest that regular consumption of green tea may prolong life expectancy and quality of life in prostate cancer patients.