Greenteahaus:  The Green Tea Reference Library

General comments by medical and scientific authorities on green tea, and the “typical green tea” as a chemopreventive beverage in cancer risk reduction

Follow links to abstracts below. Complete bibliography information may be used to obtain a full copy of the article at your local library.
Return to Reference Library Index

1 Role of diet modification in cancer prevention. Biofactors. 2000;12(1-4):45-51.
2 Green tea polyphenols and cancer: biologic mechanisms and practical implications. Nutr Rev. 1999 Mar;57(3):78-83.
3 Studies on biomarkers in cancer etiology and prevention: a summary and challenge of 20 years of interdisciplinary research. Mutat Res. 2000 Apr;462(2-3):255-79.
4 Novel approaches to chemoprevention of skin cancer. J Dermatol 2000;27:691-5.
5 Tea and cancer: a review of the epidemiological evidence. Eur J Cancer Prev. 1996 Dec;5(6):425-38.
6 Green tea and cancer in humans: a review of the literature. Nutr Cancer. 1998;31(3):151-159.
7 Tonic in a teapot. Consum Rep 2003 Mar;68(3):40-3.
8 Health-promoting properties of common herbs. Am J Clin Nutr. 1999 Sep;70(3 Suppl):491S-499S.
9 Green tea catechins as novel antitumor and antiangiogenic compounds. Curr Med Chem Anti-Canc Agents. 2002 Jul;2(4):441-63.
10 Cancer inhibition by green tea. Mutat Res. 1998 Jun 18;402(1-2):307-10.
11 Two stages of cancer prevention with green tea. J Cancer Res Clin Oncol. 1999;125(11):589-97.
12 New TNF-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen. Mutat Res 2003;523-524:119-125.
13 Japanese green tea as a cancer preventive in humans. Nutr Rev 1996 Nov;54(11 Pt 2):S67-70 Saitama Cancer Center Research Institute, Japan.
14 Involvement of TNF-alpha changes in human cancer development, prevention and palliative care. Mech Ageing Dev. 2002 Nov;123(12):1655-63.
15 A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review. Cancer Detect Prev. 2000;24(1):91-9.
16 Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr. 2003;43(1):89-143.
17 Potential molecular targets of tea polyphenols in human tumor cells: significance in cancer prevention. In Vivo 2002;16:397-403.
18 Progress in cancer chemoprevention. Ann N Y Acad Sci. 1999;889:1-13.
19 Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr. 2000 Feb;130(2S Suppl):467S-471S.
20 Total phenol, catechin, and caffeine contents of teas commonly consumed in the United Kingdom. J Agric Food Chem. 2002 Jan 30;50(3):565-70.
21 Tea and cancer prevention: an evaluation of the epidemiologic literature. Nutr Cancer 1997;27(1):1-13.
22 Food temperature and gastric cancer. Int J Cancer. 1990 Sep 15;46(3):432-4.
23 A case-control study of diet and colo-rectal cancer in northern Italy. Int J Cancer. 1988 Apr 15;41(4):492-8.
24 Cancer preventive effects of flavonoids--a review. Biomed Pharmacother 2002; 56:296-301.
25 Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis? Med Hypotheses. 1998 May;50(5):423-33.
26 Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci. 2001 Apr;928:226-35.
27 Green tea in chemoprevention of cancer. Toxicol Sci. 1999 Dec;52(2 Suppl):111-7.
28 Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr 2000;71(6 Suppl):1698S-702S; discussion 1703S-4S.
29 Clinical development plan: tea extracts green tea polyphenols epigallocatechin gallate. J Cell Biochemistry 1996;26S:236-257.
30 Botanicals in cancer chemoprevention. Cancer Metastasis Rev. 2002;21(3-4):231-55.
31 Coffee and tea consumption in relation to the risk of large bowel cancer: a review of epidemiologic studies. Cancer Lett. 1990 Jul 31;52(3):163-71.
32 Green tea and gastric cancer. N Engl J Med 2001;344:675-6.
33 Chemopreventive effect of green tea (Camellia sinensis) among cigarette smokers. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):387-91.
34 The state-of-the-art in chemoprevention of skin cancer. Eur J Cancer 2000;36:1292-7.
35 A new function of green tea: prevention of lifestyle-related diseases. Ann N Y Acad Sci. 2001 Apr; 928:274-80.
36 Combination cancer chemoprevention with green tea extract and sulindac shown in intestinal tumor formation in Min mice. J Cancer Res Clin Oncol 2001;127:69-72.
37 Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480-481:243-68.
38 ‘Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 2002;16:2-14.
39 Dietary differences with green tea intake among middle-aged Japanese men and women. Prev Med 1997 Sep-Oct;26(5 Pt 1):704-10
40 Green tea experiments in lab, clinic yield mixed results. J Natl Cancer Inst 2000 ;92:1038-9.
41 Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food Chem Toxicol 2002;40:1145-54.
42 Approaches for chronic disease prevention based on current understanding of underlying mechanisms. Am J Clin Nutr 2000;71(6 Suppl):1710S-4S; discussion 1715S-9S.
43 Lifestyle, health and disease prevention: the underlying mechanisms. Eur J Cancer Prev. 2002 Aug;11 Suppl 2:S1-S7.
44 Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol. 1999 Sep-Oct;37(9-10):943-8.
45 Tea and health: a historical perspective. Cancer Lett. 1997 Mar 19;114(1-2):315-7.
46 Tea and health: the underlying mechanisms. Proc Soc Exp Biol Med. 1999 Apr;220(4):271-5.
47 Worldwide prevention of cancer and other chronic diseases based on knowledge of mechanisms. Mutat Res. 1998 Jun 18;402(1-2):331-7.
48 Tea and cancer. J Natl Cancer Inst. 1993 Jul 7;85(13):1038-49.
49 Modification of lung cancer susceptibility by green tea extract as measured by the comet assay. Cancer Detect Prev. 2002;26(6):411-8.

Abstracts
Return to Reference Library Index

1 Abdulla M, Gruber P. Role of diet modification in cancer prevention. Biofactors. 2000;12(1-4):45-51.

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and include both genetic and biochemical changes in the cells. At each of these levels, there are several possibilities of intervention in order to prevent, slow down or even halt the gradual march of healthy cells towards malignancy. Diet modification is one such possibility. A number of natural foodstuffs, especially fruits and vegetables contain substantial quantities of molecules that have chemopreventive potential against cancer development. Such compounds include vitamins, trace elements and a variety of other molecules with antioxidant properties. Carotenoids, flavanoid polyphenols, isoflavones, catechins, and several other components that found in cruciferous vegetables are molecules that are known to protect against the deleterious effect of reactive oxygen species. A number of epidemiological and experimental studies have shown that vitamin C and E, Beta-carotene and the essential trace element selenium can reduce the risk of cancer. Consistent observations during the last few decades that cancer risk is reduced by a diet rich in vegetables, fruits, legumes, grains and green tea have encouraged research to identify several plant components especially phytochemicals that protect against DNA damage. Many of these substances block specific carcinogen pathways. Dietary supplements are part of an overall health program, along with a high intake of fruits and vegetables that help to combat damage to cells, which in turn may initiate cancer development. This paper will review current knowledge concerning diet modification and cancer prevention with special reference to minerals and trace elements.
Return to top ↑

2 Ahmad N, Mukhtar H. Green tea polyphenols and cancer: biologic mechanisms and practical implications. Nutr Rev. 1999 Mar;57(3):78-83.

Polyphenolic compounds in fruits and vegetables have been associated with lower risk of some diseases, including cancer. Recent research has shown that the polyphenolic antioxidants in green tea possess cancer chemopreventive effects. This review discusses the cancer chemopreventive effects associated with green tea and the molecular mechanisms that underlie the broad anticarcinogenic effect of polyphenols in green tea.
Return to top ↑

3 Bartsch H. Studies on biomarkers in cancer etiology and prevention: a summary and challenge of 20 years of interdisciplinary research. Mutat Res. 2000 Apr;462(2-3):255-79.

Sensitive, specific methods have been developed that allow quantitative measurements of the metabolites of carcinogen metabolites and of DNA and protein adducts in humans exposed occupationally, environmentally and endogenously to genotoxic agents. The interrelationship between exposure to carcinogens, host risk factors and the responses of biomarkers has been examined in cross-sectional, ecological and case-control studies which provided new insights into the causes of cancer and the mechanisms of carcinogenesis. The identification of hitherto unknown DNA-reactive chemicals formed in the human body from dietary precursors and of carcinogenic components of complex mixtures has increased the possibility of establishing causal relationships in etiology. The identification of individuals and subgroups heavily exposed to carcinogens has led to the development of measures for avoiding or decreasing exposure to carcinogenic risk factors. New, ultrasensitive methods for measuring DNA adducts allow the quantification and structural elucidation of specific DNA damage in humans arising from oxidative stress and lipid peroxidation (LPO), which have been found to be the driving forces in several human malignancies. Background DNA damage in "unexposed" individuals has been shown unequivocally to be due to LPO products, and a significant interindividual variation in adduct levels has been shown in individuals with comparable exposure to carcinogens. Thus, pharmacogenetic variants with higher susceptibility to carcinogenic insults, due to genetic polymorphism in xenobiotic-metabolizing enzymes, have been characterized by a combination of genotyping and measurements of macromolecular adducts. Dosimetry has been used in human studies to evaluate the efficacy of interventions with chemopreventive agents like ascorbic acid, dietary phenols and green tea. Advances in the application of selected biomarkers in human studies are reviewed and illustrated by examples from the author's research conducted during the past two decades.
Return to top ↑

4 Bickers DR, Athar M. Novel approaches to chemoprevention of skin cancer. J Dermatol 2000;27:691-5.

We demonstrated that green tea, black tea and constituent polyphenols protect against chemical- and ultraviolet B (UVB)-induced carcinogenesis and reduce the growth of established tumors in skin. We have also shown the efficacy of green and black tea extracts against UVB and psoralen + ultraviolet A (PUVA)-induced early damage in skin. Although PUVA is highly effective in treating certain skin diseases, careful follow-up studies of cohorts of patients have shown that similar to UVB, PUVA treatment increases the risk for cutaneous squamous cell carcinoma and melanoma. We have found that oral administration of a standardized green tea extract (SGTE) prior to and during treatment of SKH-1 mice diminished PUVA-induced skin hyperplasia and hyperkeratosis. SGTE-treatment also inhibited PUVA-induced accumulation of c-fos and p53 proteins and epithelial hyperproliferation. Both topical application and oral administration of SGTE after PUVA-treatment reduced skin inflammation and cell hyperproliferation. Topical application of SGTE to human skin prior to PUVA-treatment inhibited the delayed skin inflammatory response. Similarly, oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic sub-fractions protect against UVB-induced erythema in SKH-1 mice. Furthermore, topical application of tea extracts to human volunteers protects against UVB-induced erythema. In summary, these studies indicate that tea extracts are effective in reducing UVB- and PUVA-mediated DNA damage, expression of early response genes and early inflammatory changes in skin. These studies verify a conceptual rationale for employing naturally occurring dietary constitutents as an approach to cancer chemoprevention.
Return to top ↑

5 Blot WJ, Chow WH, McLaughlin JK. Tea and cancer: a review of the epidemiological evidence. Eur J Cancer Prev. 1996 Dec;5(6):425-38.

Numerous recent reports of inhibition of carcinogenesis in experimental animals by tea or tea compounds raise the possibility that tea drinking may lower cancer risk in humans. Thus, studies around the world were reviewed to evaluate whether there is a consensus of epidemiologic evidence on the relation of tea drinking to cancer overall or to specific cancers. Ecological data suggest at most a modest benefit, since there is considerable international variation in tea consumption but generally small differences in cancer rates. More relevant case-control and cohort studies show mixed results. Detailed data from these studies on cancer risks according to amount and duration of tea intake are quite limited, and consistent dose-related patterns. have yet to emerge. Nevertheless, several investigations point to the possibility of lowered risks of digestive tract cancers among tea drinkers, especially those consuming green tea. Further research, particularly in population with wide ranges of tea consumption, is needed before definitive conclusions on tea's impact upon cancer risk can be reached.
Return to top ↑

6 Bushman JL. Green tea and cancer in humans: a review of the literature. Nutr Cancer. 1998;31(3):151-159.

Researchers have investigated green tea as a potential protectant against cancer. This review focuses on studies of green tea in humans. Green tea contains polyphenols, chemicals that act as powerful antioxidants. Epidemiological and human studies have shown varying results. Thirty-one human studies and four reviews were examined. Among five studies reporting on colon cancer, three found an inverse association and one reported a positive association. For rectal cancer, only one of four studies reported an inverse association; increased risks were seen in two of the studies. An inverse association is suggested for urinary bladder cancer in two of two studies. Of 10 studies examining the association of green tea and stomach cancer, 6 suggest an inverse and 3 a positive association. The most comprehensive of these studies supports an inverse association of green tea and stomach cancer. Pancreatic cancer studies hint at an inverse association in two of three studies. A strong inverse effect was found with green tea and esophageal cancer. Lung cancer studies have shown an inverse effect with Okinawan tea, yet tentatively increased risk was shown in another study. Although human studies have their limitations, the research has warranted a further look into the effects of green tea and cancer.
Return to top ↑

7 Tonic in a teapot. Consum Rep 2003 Mar;68(3):40-3.

Here's the latest evidence tea is good for you and, because you have to drink it to reap the benefits, our taste tests of 19 green teas.
Return to top ↑

8 Craig WJ. Health-promoting properties of common herbs. Am J Clin Nutr. 1999 Sep;70(3 Suppl):491S-499S.

Herbs have been used as food and for medicinal purposes for centuries. Research interest has focused on various herbs that possess hypolipidemic, antiplatelet, antitumor, or immune-stimulating properties that may be useful adjuncts in helping reduce the risk of cardiovascular disease and cancer. In different herbs, a wide variety of active phytochemicals, including the flavonoids, terpenoids, lignans, sulfides, polyphenolics, carotenoids, coumarins, saponins, plant sterols, curcumins, and phthalides have been identified. Several of these phytochemicals either inhibit nitrosation or the formation of DNA adducts or stimulate the activity of protective enzymes such as the Phase II enzyme glutathione transferase (EC 2.5.1.18). Research has centered around the biochemical activity of the Allium sp. and the Labiatae, Umbelliferae, and Zingiberaceae families, as well as flaxseed, licorice root, and green tea. Many of these herbs contain potent antioxidant compounds that provide significant protection against chronic diseases. These compounds may protect LDL cholesterol from oxidation, inhibit cyclooxygenase and lipoxygenase enzymes, inhibit lipid peroxidation, or have antiviral or antitumor activity. The volatile essential oils of commonly used culinary herbs, spices, and herbal teas inhibit mevalonate synthesis and thereby suppress cholesterol synthesis and tumor growth.
Return to top ↑

9 Demeule M, Michaud-Levesque J, Annabi B, Gingras D, Boivin D, Jodoin J, Lamy S, Bertrand Y, Beliveau R. Green tea catechins as novel antitumor and antiangiogenic compounds. Curr Med Chem Anti-Canc Agents. 2002 Jul;2(4):441-63.

The concept of cancer prevention by use of naturally occuring substances that could be included in the diet is under investigation as a practical approach towards reducing cancer incidence, and therefore the mortality and morbidity associated with this disease. Tea, which is the most popularly consumed beverage aside from water, has been particularly associated with decreased risk of various proliferative diseases such as cancer and atherosclerosis in humans. Various studies have provided evidence that polyphenols are the strongest biologically active agents in green tea. Green tea polyphenols (GTPs) mainly consist of catechins (3-flavanols), of which (-)-epigallocatechin gallate is the most abundant and the most extensively studied. Recent observations have raised the possibility that green tea catechins, in addition to their antioxidative properties, also affect the molecular mechanisms involved in angiogenesis, extracellular matrix degradation, regulation of cell death and multidrug resistance. This article will review the effects and the biological activities of green tea catechins in relation to these mechanisms, each of which plays a crucial role in the development of cancer in humans. The extraction of polyphenols from green tea, as well as their bioavailability, are also discussed since these two important parameters affect blood and tissue levels of the GTPs and consequently their biological activities. In addition, general perspectives on the application of dietary GTPs as novel antiangiogenic and antitumor compounds are also presented.
Return to top ↑

10 Fujiki H, Suganuma M, Okabe S, Sueoka N, Komori A, Sueoka E, Kozu T, Tada Y, Suga K, Imai K, Nakachi K. Cancer inhibition by green tea. Mutat Res. 1998 Jun 18;402(1-2):307-10.

Green tea is now an acknowledged cancer preventive in Japan. This paper discusses several important features of (-)-epigallocatechin gallate (EGCG), the main constituent of green tea and tea polyphenols. EGCG and other tea polyphenols inhibited growth of human lung cancer cell line, PC-9 cells with G2/M arrest. 3H-EGCG administered by p.o. intubation into mouse stomach revealed that small amounts of 3H-activity were found in various organs where EGCG and green tea extract had previously demonstrated their anticarcinogenic effects, such as skin, stomach, duodenum, colon, liver, lung and pancreas. Cancer onset of patients who had consumed over 10 cups of green tea per day was 8.7 years later among females and 3.0 years later among males, compared with patients who had consumed under three cups per day. The mechanisms of action of EGCG were briefly discussed with regard to inhibition of tumor necrosis factor-alpha (TNF-alpha) release.
Return to top ↑

11 Fujiki H. Two stages of cancer prevention with green tea. J Cancer Res Clin Oncol. 1999;125(11):589-97.

Cancer chemoprevention is a new and important medical science in its own right. On the occasion of my presentation entitled "Natural agents and cancer chemoprevention" at the 90th AACR Meeting in 1999, I summarized our recent results on cancer prevention with green tea. In this article, the present status of clinical trials supported by the Chemoprevention Branch of the National Cancer Institute in the United States is first described by way of introduction. Although various natural products are now under investigation in phase I clinical trials, green tea has, perhaps, the greatest potential for further development. In order to expand our understanding of the effects of tea polyphenols and green tea, I review their ability to inhibit growth and cause apoptosis of cancer cells, their distribution into target organs and their other cancer-preventing properties. In addition, the paper focuses on the significance of reducing tumor necrosis factor alpha (TNFalpha) gene expression in cells and TNFalpha release from cells as essential activities for cancer prevention. As for the amounts of green tea effective in cancer prevention, I present two results from our Research Institute: a prospective cohort study with over 8000 individuals in Saitama Prefecture revealed that the daily consumption of at least ten Japanese-size cups of green tea resulted in delayed cancer onset, and a follow-up study of breast cancer patients conducted at our Hospital found that stages I and II breast cancer patients consuming over five cups per day experienced a lower recurrence rate and longer disease-free period than those consuming fewer than four cups per day. Thus, I propose here, for the first time, the two-stage approach to analyzing cancer prevention with green tea: cancer prevention before cancer onset and cancer prevention following cancer treatment. As an additional example of cancer prevention with natural agents, kava, a daily beverage in Fiji, is mentioned. All the evidence reminds us of the significance of alternative medicine in practical cancer prevention.
Return to top ↑

12 Fujiki H, Suganuma M, Kurusu M, Okabe S, Imayoshi Y, Taniguchi S, Yoshida T. New TNF-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen. Mutat Res 2003;523-524:119-125.

Herbal medicines are now attracting attention as potential sources of cancer preventive agents. Based on accumulated results of green tea as a cancer preventive, the authors review two important results with EGCG: the synergistic effects of EGCG with sulindac or tamoxifen on cancer preventive activity in PC-9 cells, and cancer prevention of intestinal tumor development in multiple intestinal neoplasia (Min) mice by cotreatment using EGCG with sulindac. Overall, the encouraging and beneficial results indicate that both clinicians and medical researchers should consider green tea as a chemopreventive herbal medicine in the fight against cancer.
Return to top ↑

13 Fujiki H, Suganuma M, Okabe S, Komori A, Sueoka E, Sueoka N, Kozu T, Sakai Y. Japanese green tea as a cancer preventive in humans. Nutr Rev 1996 Nov;54(11 Pt 2):S67-70 Saitama Cancer Center Research Institute, Japan.

In the opinions of the authors, green tea is now generally acknowledged as a dietary supplement to prevent cancer in Japan.
Return to top ↑

14 Fujiki H, Suganuma M, Okabe S, Kurusu M, Imai K, Nakachi K. Involvement of TNF-alpha changes in human cancer development, prevention and palliative care. Mech Ageing Dev. 2002 Nov;123(12):1655-63.

Cancer development and ageing are complex sciences. From the study on the process of rodent carcinogenesis, we identified tumor necrosis factor-alpha (TNF-alpha) as an important mediator of cancer development. This paper presents three clinical examples of TNF-alpha up-regulation: by cord factors of Mycobacterium tuberculosis, such as trehalose 6-monomycolate, as an activator of protein kinase C and by a cord factor like fraction of Microsporum canis obtained in the air inside houses in Thailand, both of which are risk factors in human lung cancer development, and by Helicobacter pylori gene product, H. pylori membrane protein 1 (HP-MP1) in relation to human stomach cancer. The second part of this paper deals with down-regulation of TNF-alpha by a wide variety of cancer preventive agents. Among the various agents, (-)-epigallocatechin gallate (EGCG) and green tea polyphenols inhibited TNF-alpha gene expression in the cells induced by tumor promoter, mediated through inhibition of NF-kappaB activation. Studying growth inhibition of human cancer cell lines by morphine, we found that morphine and the new morphine derivatives KT-90 and KT-87 have anticancer activity mediated through induction of apoptosis, in addition to analgesic action. We conclude that environmental and endogenous factors induce NF-kappaB activation mediated through expression of inflammatory cytokine genes, such as TNF-alpha, and that the expression pattern of the genes operates similarly in the aging process.
Return to top ↑

15 Fujiki H, Suganuma M, Okabe S, Sueoka E, Suga K, Imai K, Nakachi K. A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review. Cancer Detect Prev. 2000;24(1):91-9.

The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters has revealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF-alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate tumor promotion and progression of initiated cells as well as premalignant cells. The first part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidence that pretreatment with agents such as tamoxifen, sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and the general population.
Return to top ↑

16 Higdon JV, Frei B. Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr. 2003;43(1):89-143.

Increasing interest in the health benefits of tea has led to the inclusion of tea extracts in dietary supplements and functional foods. However, epidemiologic evidence regarding the effects of tea consumption on cancer and cardiovascular disease risk is conflicting. While tea contains a number of bioactive chemicals, it is particularly rich in catechins, of which epigallocatechin gallate (EGCG) is the most abundant. Catechins and their derivatives are thought to contribute to the beneficial effects ascribed to tea. Tea catechins and polyphenols are effective scavengers of reactive oxygen species in vitro and may also function indirectly as antioxidants through their effects on transcription factors and enzyme activities. The fact that catechins are rapidly and extensively metabolized emphasizes the importance of demonstrating their antioxidant activity in vivo. In humans, modest transient increases in plasma antioxidant capacity have been demonstrated following the consumption of tea and green tea catechins. The effects of tea and green tea catechins on biomarkers of oxidative stress, especially oxidative DNA damage, appear very promising in animal models, but data on biomarkers of in vivo oxidative stress in humans are limited. Larger human studies examining the effects of tea and tea catechin intake on biomarkers of oxidative damage to lipids, proteins, and DNA are needed.
Return to top ↑

17 Kazi A, Smith DM, Daniel K, Zhong S, Gupta P, Bosley ME, Dou QP. Potential molecular targets of tea polyphenols in human tumor cells: significance in cancer prevention. In Vivo 2002;16:397-403.

Epidemiological studies have shown decreased cancer occurrence in those individuals who drink green tea regularly. A wealth of research suggests numerous mechanisms of action to explain these observations. The most abundant and popular compound studied in tea research is (-)-epigallocatechin-3-gallate (EGCG), which acts as a powerful antioxidant and can inhibit a number of tumor cell proliferation- and survival-related proteins. Tea polyphenols are known to inhibit the large multi-catalytic protease (the proteasome) and metaloproteionases, involved in tumor survival and metastasis, respectively. Additionally, tea polyphenols inhibit the activities of many tumor-associated protein kinases, including epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, mitogen-activated protein kinase, and IkB kinase. Tea polyphenols have also been found to inhibit some cancer-related proteins that regulate DNA replication and transformation. At present, it is not known which of these activities of tea polyphenols are required for its cancer-preventive effects.
Return to top ↑

18 Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Boone CW, Malone WA, Hawk ET, Lieberman R, Lawrence JA, Kopelovich L, Ali I, Viner JL, Sigman CC. Progress in cancer chemoprevention. Ann N Y Acad Sci. 1999;889:1-13.

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).
Return to top ↑

19 Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Malone WA, Boone CW, Kopelovich L, Hawk ET, Lieberman R, Lawrence JA, Ali I, Viner JL, Sigman CC. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. J Nutr. 2000 Feb;130(2S Suppl):467S-471S.

Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention.
Return to top ↑

20 Khokhar S, Magnusdottir SG. Total phenol, catechin, and caffeine contents of teas commonly consumed in the United Kingdom. J Agric Food Chem. 2002 Jan 30;50(3):565-70.

Levels of total phenol, catechins, and caffeine in teas commonly consumed in the United Kingdom have been determined using reversed phase high-performance liquid chromatography. Tea bags or tea leaves were purchased from local supermarkets and extracted in boiling water for 5 min. The resulting data showed considerable variability in both total phenols [80.5-134.9 mg/g of dry matter (DM) in black teas and 87-106.2 mg/g of DM in green teas] and catechins (5.6-47.5, 51.5-84.3, and 8.5-13.9 mg/g of DM in black, green, and fruit teas, respectively); this was most probably a result of differing agronomic conditions, leaf age, and storage during and after transport, as well as the degree of fermentation. Caffeine contents of black teas (22-28 mg/g of DM) were significantly higher than in less fermented green teas (11-20 mg/g of DM). The relative concentration of the five major tea catechins ranked EGCG > ECG > EC > EGC > C. The estimated U.K. dietary intakes of total tea catechins, calculated on the basis of an average tea consumption of three cups of tea (200 mL cup, 1% tea leaves w/v), were 61.5, 92.7, and 405.5 mg/day from fruit teas, black teas, and green teas, respectively. The coefficients of variation were 19.4, 88.6, and 17.3%, respectively, indicating the wide variation in these intakes. The calculated caffeine intake ranged between 92 and 146 mg/day. In addition, many individuals will consume much larger quantities of tea, of various strengths (as determined by the brewing conditions employed). This broad spread of U.K. daily intakes further emphasizes the need for additional research to relate intake and effect in various population groups.
Return to top ↑

21 Kohlmeier L, Weterings KG, Steck S, Kok FJ. Tea and cancer prevention: an evaluation of the epidemiologic literature. Nutr Cancer 1997;27(1):1-13.

Animal and in vitro studies provide evidence of an anticarcinogenic potential of active ingredients in teas. This review encompasses epidemiologic studies of stomach, colon, and lung cancer as well as the evidence of a relationship between tea drinking and cancer at large in humans. Cohort studies do not suggest a protective role for tea drinking in the total risk of cancer. Site-specific studies reveal a more complex picture. The epidemiologic studies on tea drinking and stomach cancer do not justify claims of a cancer-protective effect. A protective effect of green tea on the development of colon cancer is suggested. The evidence regarding black tea is less clear, with some indication of a risk of colon or rectal cancer associated with regular use of black tea. The studies on tea and lung cancer also suggest an increased risk with increased tea consumption. The range and crude categorization of tea consumption, choice of control groups, and inadequate control for confounding might have obscured possible relationships. From the limited studies that suggest a favorable effect from tea, it is likely that benefits are restricted to high intakes in high-risk populations.
Return to top ↑

22 (22) La Vecchia C, Negri E, D'Avanzo B, Franceschi S. Food temperature and gastric cancer. Int J Cancer. 1990 Sep 15;46(3):432-4.

The relationship between preference for food temperature and the risk of stomach cancer was analysed using data from a case-control study conducted in Northern Italy on 563 histologically confirmed incident gastric cancers and 1,501 controls admitted to hospital for acute, non-neoplastic, non-digestive tract disorders. A specific question was related to food temperature, subjectively defined as "warm", "hot" or "very hot". Compared with subjects indicating preference for "warm" foods, the relative risk (RR) was 1.1 (95% confidence interval, CI, 0.9-1.4) for "hot" and 1.8 (95% CI = 1.3-2.4) for "very hot". The test for trend in risk was statistically significant, and the results were not appreciably modified by allowance for a number of identified potential distorting factors. The elevated risk, however, appeared to be restricted to the 17% of cases reporting a preference for "very hot" foods. This may be due to an absence of substantial misclassification between "warm" and "very hot", but also to the existence of a threshold temperature, below which no appreciable thermal irritation is evident. Thus, although the difficulties and uncertainties on measures of food temperature are substantial, these data suggest that thermal irritation may have a role in gastric carcinogenesis.
Return to top ↑

23 La Vecchia C, Negri E, Decarli A, D'Avanzo B, Gallotti L, Gentile A, Franceschi S. A case-control study of diet and colo-rectal cancer in northern Italy. Int J Cancer. 1988 Apr 15;41(4):492-8.

The relation between dietary factors and the risk of colorectal cancer was investigated in a case-control study conducted in Northern Italy on 339 cases of colon cancer, 236 cases of rectal cancer and 778 controls admitted to hospital for acute, non-neoplastic or digestive disorders. Consistent positive associations were observed with more frequent consumption of starchy foods (pasta or rice) (relative risk, RR = 3.0 for colon and 1.8 for rectum for highest vs. lowest tertile) and beef/veal meats (RR = 2.1 for colon, 2.3 for rectum), whereas reduced relative risks were observed in subjects reporting more frequent green vegetable consumption (RR = 0.5 for highest vs. lowest tertile), a few specific vegetable or fruit items, and coffee (RR = 0.6 for highest vs. lowest tertile). Various fats in seasonings were positively, but inconsistently, related to intestinal cancer risk, whereas no association was evident with measures of whole grain foods or alcohol intake. For both intestinal sites, a 4- to 5-fold difference in risk was evident between the extreme quintiles of a simple score obtained by algebraic sum of the 4 major groups of foods. These findings could not be explained in terms of confounding by socio-economic status or other major potential distorting factors, are in agreement with the results from previous studies of colo-rectal cancer in Southern Europe, and are consistent with various aspects of the descriptive epidemiology of intestinal cancer in Italy.
Return to top ↑

24 Le Marchand L. Cancer preventive effects of flavonoids--a review. Biomed Pharmacother 2002; 56:296-301.

A cancer protective effect from plant-derived foods has been found with uncommon consistency in epidemiologic studies. However, it has been difficult to identify specific components responsible for this effect. Many phytochemicals have been shown to be biologically active and they may interact to protect against cancer. In recent years, experimental studies have provided growing evidence for the beneficial action of flavonoids on multiple cancer-related biological pathways (carcinogen bioactivation, cell signaling, cell cycle regulation, angiogenesis, oxidative stress, inflammation). Although the epidemiologic data on flavonoids and cancer are still limited and conflicting, some protective associations have been suggested for flavonoid-rich foods (soy and premenopausal breast cancer; green tea and stomach cancer; onion and lung cancer). This review focuses on the biological effects of the main flavonoids, as well as the epidemiologic evidence that support their potential cancer protective properties.
Return to top ↑

25 McCarty MF. Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis? Med Hypotheses. 1998 May;50(5):423-33.

It is increasingly clear that apoptosis plays a crucial role in the promotional phase of cancer development. Initiated pre-neoplastic clones in rat liver experience a high rate of apoptosis, and this rate has an important impact on the survival and growth of these clones. Suppression of apoptosis appears to be a universal property of cancer promoters, suggesting conversely that agents which inhibit cancer induction during the promotional phase increase the rate of apoptosis in initiated cells. Modulation of apoptosis is a likely explanation for recent striking evidence that use of calcium channel blockers substantially increases, whereas supplemental selenium substantially decreases, human cancer incidence. Non-genotoxic measures which are likely to upregulate apoptosis in pre-neoplastic/neoplastic cells--and thus may be useful in prevention and/or therapy--include selenium, retinoids/carotenoids, green tea polyphenols, caloric restriction, downregulation of IGF-I activity, high-dose tamoxifen and other protein kinase C antagonists, withdrawal or blockade of trophic hormones, isoflavones, limonene, vitamin D and cholecalciferol analogs, dietary fiber/sodium butyrate, hyperthermia, benzaldehyde derivatives, and creatine.
Return to top ↑

26 Meydani M. Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci. 2001 Apr;928:226-35.

The nutritional status and needs of elderly people are associated with age-related biological and often socioeconomic changes. Decreased food intake, a sedentary lifestyle, and reduced energy expenditure in older adults altogether become critical risk factors for malnutrition, especially protein and micronutrients. Surveys indicate that the elderly are particularly at risk for marginal deficiency of vitamins and trace elements. Changes in bodily functions, together with the malnutrition associated with advancing age, increase the risk of developing a number of age-related diseases. Chronic conditions pose difficulties for the elderly in carrying out the activities of daily living and may increase the requirements for certain nutrients due to changes in absorptive and metabolic capacity. Free radicals and oxidative stress have been recognized as important factors in the biology of aging and of many age-associated degenerative diseases. In this regard, modulation of oxidative stress by calorie restriction, as demonstrated in animal models, is suggested as one mechanism to slow the aging process and the decline of body functions. Therefore, dietary components with antioxidant activity have received particular attention because of their potential role in modulating oxidative stress associated with aging and chronic conditions. Several studies have indicated potential roles for dietary antioxidants in the reduction of degenerative disease such as vascular dementia, cardiovascular disease, and cancer. In support of epidemiological studies, our recent studies indicate that the antioxidant properties of vitamin E and polyphenols present in green tea may contribute to reducing the risk of cardiovascular disease, in part by reducing the susceptibility of low density lipoproteins to oxidation, decreasing the vascular endothelial cell expression of pro-inflammatory cytokines, and decreasing the expression of adhesion molecules and monocyte adhesion. Recently, we also demonstrated that these dietary antioxidants may have a preventive role in cancer, potentially through the suppression of angiogenesis by inhibiting interleukin-8 production and the cell junction molecule VE-cadherin. These findings concur with epidemiologic, clinical, and animal studies suggesting that the consumption of green tea and vitamin E is associated with a reduced risk of cardiovascular disease and cancer, the leading causes of morbidity and mortality among the elderly.
Return to top ↑

27 Mukhtar H, Ahmad N. Green tea in chemoprevention of cancer. Toxicol Sci. 1999 Dec;52(2 Suppl):111-7.

The concept of prevention of cancer using naturally occurring substances that could be included in the diet consumed by the human population is gaining increasing attention. Tea, next to water, is the most popularly consumed beverage in the world and it is grown in about 30 countries. Abundant data, amassed from several laboratories around the world in the last ten years, provided convincing evidence that polyphenolic antioxidants present in tea afford protection against cancer risk in many animal-tumor bioassay systems. The epidemiological studies, though inconclusive, have also suggested that the consumption of tea is associated with a lowered risk of cancer. Much of this work has been done on green tea; less is known about black tea. Green tea contains many polyphenolic antioxidants, and (-)-epigallocatechin-3-gallate (EGCG) is the key polyphenolic antioxidant believed to be responsible for most of the cancer chemopreventive properties of green tea. This review will discuss these effects and the molecular mechanisms associated with the biological response to green-tea polyphenols.
Return to top ↑

28 Mukhtar H, Ahmad N. Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr 2000;71(6 Suppl):1698S-702S; discussion 1703S-4S.

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 > or =10 cups (> or =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.
Return to top ↑

29 NCI, DCPC, Chemoprevention Branch and Agent Development Committee, Clinical development plan: tea extracts green tea polyphenols epigallocatechin gallate. J Cell Biochemistry 1996;26S:236-257.

Page 245 stated: …a typical cup of green tea (200 ml, gun powder, Hangzhou, China) contains 142 mg EGCG, 65 mg epigallocatechin, 28 mg epicatechin gallate, 17 mg epicatechin and 76 mg caffeine…
Return to top ↑

30 Park EJ, Pezzuto JM. Botanicals in cancer chemoprevention. Cancer Metastasis Rev. 2002;21(3-4):231-55.

Botanicals have been used for the treatment of various human diseases throughout history. In addition, botanicals play a role in disease prevention. For example, epidemiologic studies have suggested that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. In this review, we discuss the cancer chemopreventive activity of cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, tomatoes, berries, ginger and ginseng, as well as some medicinal plants. In addition, methods for the discovery of active compounds from plant sources are described. Several lead compounds, such as brassinin (from cruciferous vegetables like Chinese cabbage), sulforaphane (from broccoli) and its analog sulforamate, withanolides (from tomatillos), and resveratrol (from grapes and peanuts among other foods), are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals of these types have great potential in the fight against human cancer, and a variety of delivery methods are available as a result of their occurrence in nature.
Return to top ↑

31 Rosenberg L. Coffee and tea consumption in relation to the risk of large bowel cancer: a review of epidemiologic studies. Cancer Lett. 1990 Jul 31;52(3):163-71.

Most of the few epidemiologic investigations of the relation of methylxanthine ingestion to risk of large bowel cancer have concerned coffee consumption. A slightly increased risk in coffee drinkers was suggested by one study, no association by another and an inverse association by four, but there was a statistically significant trend across levels of consumption in only one of the latter studies. Based on the data on hand, there is little reason for concern that coffee consumption increases the risk. Although some evidence suggests an inverse association, the data are not compelling and a biologic mechanism is not established. There is even less information on tea consumption and the relation of consumption of this beverage to risk of large bowel cancer is unknown.
Return to top ↑

32 Sano T, Sasako M. Green tea and gastric cancer. N Engl J Med 2001;344:675-6.

Several confounding factors may be considered in explaining the lack of chemopreventive effects of green tea consumption against the incidence of stomach cancer as reported by 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;344(9):632-6
Return to top ↑

33 Shim JS, Kang MH, Kim YH, Roh JK, Roberts C, Lee IP. Chemopreventive effect of green tea (Camellia sinensis) among cigarette smokers. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):387-91.

Chemopreventive effects of green tea and coffee among cigarette smokers were examined in 52 clinically healthy male subjects between 20 and 52 years of age. Blood specimens were obtained from nonsmokers (group I), smokers (group II), smokers consuming green tea (group III), and smokers drinking coffee (group IV). The mean number of cigarette smoking years (> 10 cigarettes/day) in groups II-IV ranged from 13.4 to 14.7 years. Daily intake of green tea and coffee was 2-3 cups/day for 6 months (groups III and IV). The frequencies of sisterchromatid exchange (SCE) in mitogen-stimulated peripheral lymphocytes from each experimental group were determined and analyzed statistically. SCE rates were elevated significantly in smokers (9.46 +/- 0.46) versus nonsmokers (7.03 +/- 0.33); however, the frequency of SCE in smokers who consumed green tea (7.94 +/- 0.31) was comparable to that of nonsmokers, implying that green tea can block the cigarette-induced increase in SCE frequency. Coffee, in contrast, did not exhibit a significant inhibitory effect on smoking-induced SCE.
Return to top ↑

34 Stratton SP, Dorr RT, Alberts DS. The state-of-the-art in chemoprevention of skin cancer. Eur J Cancer 2000;36:1292-7.

The incidence of skin cancer (both melanoma and non-melanoma) continues to grow at an alarming rate. The chemoprevention strategies proposed by the authors include the development of novel agents evaluated by (1) preclinical mechanistic studies in models of ultraviolet (UV) radiation-induced skin carcinogenesis; (2) clinical studies of immunohistochemical surrogate endpoint biomarkers in high-risk patients; and (3) randomised, placebo-controlled phase I, II and III clinical chemoprevention trials. Recent clinical results validate this development model. Molecular targets of chemopreventive strategies for melanoma and non-melanoma skin cancers include the ras and activator protein-1 (AP-1) signal transduction pathways. A transgenic murine melanoma model has been developed for evaluating potential agents in vivo. Agents at various stages of study include the green tea catechin epigallocatechin gallate (EGCG), the limonene derivative perillyl alcohol, the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO), selenium, retinoids and salicylates. New chemopreventive agents that can be used to complement sunscreens may result in decreased incidence, morbidity and mortality of skin cancer.
Return to top ↑

35 Sueoka N, Suganuma M, Sueoka E, Okabe S, Matsuyama S, Imai K, Nakachi K, Fujiki H. A new function of green tea: prevention of lifestyle-related diseases. Ann N Y Acad Sci. 2001 Apr; 928:274-80.

In the normal human life span, there occur lifestyle-related diseases that may be preventable with nontoxic agents. This paper deals with the preventive activity of green tea in some lifestyle-related diseases. Green tea is one of the most practical cancer preventives, as we have shown in various in vitro and in vivo experiments, along with epidemiological studies. Among various biological effects of green tea, we have focused on its inhibitory effect on TNF-alpha gene expression mediated through inhibition of NF-kappaB and AP-1 activation. Based on our recent results with TNF-alpha-deficient mice, TNF-alpha is an endogenous tumor promoter. TNF-alpha is also known to be a central mediator in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. We therefore hypothesized that green tea might be a preventive agent for chronic inflammatory diseases. To test this hypothesis, TNF-alpha transgenic mice, which overexpress TNF-alpha only in the lungs, were examined. The TNF-alpha transgenic mouse is an animal model of human idiopathic pulmonary fibrosis which also frequently develops lung cancer. Expressions of TNF-alpha and IL-6 were inhibited in the lungs of these mice after treatment with green tea in drinking water for 4 months. In addition, judging from the results of a prospective cohort study in Saitama Prefecture, Japan, green tea helps to prevent cardiovascular disease. In this study, a decreased relative risk of death from cardiovascular disease was found for people consuming over 10 cups of green tea a day, and green tea also had life-prolonging effects on cumulative survival. These data suggest that green tea has preventive effects on both chronic inflammatory diseases and lifestyle-related diseases (including cardiovascular disease and cancer), resulting in prolongation of life span.
Return to top ↑

36 Suganuma M, Ohkura Y, Okabe S, Fujiki H. Combination cancer chemoprevention with green tea extract and sulindac shown in intestinal tumor formation in Min mice. J Cancer Res Clin Oncol 2001;127:69-72.

Green tea is the most effective beverage for cancer prevention in humans. Looking at the concept of combination cancer chemoprevention, we previously reported the synergistic effects of (-)-epigallocatechin gallate (EGCG) with sulindac, and the additive effects of EGCG with tamoxifen, on cancer-preventive activity in human lung cancer cell line PC-9. This paper reports confirmation of the synergistic effects of EGCG with sulindac on the inhibition of intestinal tumors in multiple intestinal neoplasia (Min) mice. Treatment with both green tea extract and sulindac significantly reduced the number of tumors from 72.3 +/- 28.3 to 32.0 +/- 18.7 tumors per mouse, a decrease of 44.3%, whereas treatment with green tea extract alone or with sulindac alone reduced it to 56.7 +/- 3.5 and 49.0 +/- 12.7, respectively. The results also indicated that green tea extract inhibited tumor growth in Min mice almost as potently as sulindac itself did. The three treated groups did not show any adenocarcinomas, whereas 10.8% of the control group did. Since cancer-preventive agents like sulindac and tamoxifen are associated with adverse effects, we discuss the possibility of non-toxic, combination cancer chemoprevention with green tea, looking at the goal of truly effective cancer prevention.
Return to top ↑

37 Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480-481:243-68.

Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.
Return to top ↑

38 Tosetti F, Ferrari N, De Flora S, Albini A. ‘Angioprevention’: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 2002;16:2-14.

The potential to block tumor growth by inhibition of the neoangiogenic process represents an intriguing approach to the treatment of solid tumors. The high proliferation rate in the tumor deprived of proper vascularization would be balanced by cell death due to lack of diffusion of nutrients and oxygen. Matrix metalloproteinases (MMPs), angiogenic growth factors, and their receptors are the main targets of an increasing number of clinical trials approved to test the tolerance and therapeutic efficacy of antiangiogenic agents. The authors showed that epigallocatechin gallate (EGCG), a flavonoid from green tea that possesses chemopreventive activity in experimental and epidemiological studies, is a potent inhibitor of MMP-2 and MMP-9. Chemopreventive agents, like green tea, could exert antiangiogenic effects aimed at controlling tumor growth, and potentially useful in the clinic.
Return to top ↑

39 Tsubono Y, Takahashi T, Iwase Y, Iitoi Y, Akabane M, Tsugane S. Dietary differences with green tea intake among middle-aged Japanese men and women. Prev Med 1997 Sep-Oct;26(5 Pt 1):704-10

BACKGROUND: Although several epidemiologic investigations have suggested a protective role of green tea against cardiovascular diseases and cancer, few studies examined how consumption of green tea was associated with intake of other dietary factors.
METHODS: In the winters of 1989-1991, 880 men ages 40-49 years were randomly sampled from the general populations of five Public Health Center districts of Japan. Response rate was 72% (n = 634). A convenience sample of 373 spouses also consented to participate. They were interviewed on the frequency of consumption of green tea and 37 food items. A 3-day weighed food record was collected from a subgroup of the subjects (207 men and 164 women) to calculate daily intake of 22 nutrient variables. Consumption of the foods and nutrients was compared with three levels of green tea intake (< 1, 1-4, and > 4 cups/days) after adjustment for potential confounders.
RESULTS: Among men, green tea was associated significantly with consumption of 10 foods (P < 0.05) and at borderline significance with 4 nutrients (P < 0.1). These foods and nutrients included fruits (apple, orange juice), vegetables (green, yellow, and pickled), total lipid, cholesterol, and carotene. Among women, green tea was associated with 6 foods and total energy.
CONCLUSION: The results indicate that consumption of green tea is associated with diets that could modify the risks of cardiovascular diseases and cancer, especially among men. When the health effects of green tea are examined by observational epidemiologic studies, potential confounding and effect modification by other dietary factors should be controlled thoroughly.
Return to top ↑

40 Webb T. Green tea experiments in lab, clinic yield mixed results. J Natl Cancer Inst 2000 ;92:1038-9.

In this report, various scientists began to pay serious attention to why green tea consumption has been associated in epidemiologic studies with decreased risk of many cancers, but other studies have suggested no benefits.
Return to top ↑

41 Weisburger JH, Chung FL. Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols. Food Chem Toxicol 2002;40:1145-54.

The active components are polyphenols, mainly epigallocatechin gallate in green tea. The tea leaf polyphenol oxidase mediates oxidation to oolong and black tea, yielding other polyphenols, theaflavin and thearubigins. There is 40-50 mg caffeine in a 160-ml cup of tea. The chemopreventive effects of tea depend on: (1) its action as an antioxidant; (2) the specific induction of detoxifying enzymes; (3) its molecular regulatory functions on cellular growth, development and apoptosis; and (4) a selective improvement in the function of the intestinal bacterial flora. Many of cancers are caused by lifestyle elements. One is cigarette and tobacco use, leading to cancer in the oral cavity, esophagus and lung, inhibited by tea. Mice administered a tobacco nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), developed significantly fewer lung tumors than controls when given green tea or its major polyphenol, epigallocatechin gallate (EGCG). Tea suppressed the formation of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in the lung DNA of mice given NNK. Gastric cancer, caused by a combination of Helicobacter pylori and salted foods, is lower in tea drinkers. Western nutritionally-linked cancers of the breast, colon, prostate and pancreas can be inhibited by tea. The formation of genotoxic carcinogens for these target organs during the cooking of meats, heterocyclic amines, and their effects were decreased by tea. Tea inhibited the formation of reactive oxygen species and radicals and induced cytochromes P450 1A1, 1A2 and 2B1, and glucuronosyl transferase. The higher formation of glucuronides represents an important mechanism in detoxification. The developmental aspects and growth of cancers through promotion are decreased by tea. The regular use of a widely available, tasty, inexpensive beverage, tea, has displayed valuable preventive properties in chronic human diseases.
Return to top ↑

42 Weisburger JH. Approaches for chronic disease prevention based on current understanding of underlying mechanisms. Am J Clin Nutr 2000;71(6 Suppl):1710S-4S; discussion 1715S-9S.

In many parts of the world, particularly in the West, the major cancers associated with dietary habits involve the postmenopausal breast, distal colon, prostate, pancreas, ovary, and endometrium. Current evidence suggests that the genotoxic carcinogens for all but the last 2 of these diseases stem from the traditional intake of fried and broiled foods such as meats. The surface of these foods contains a class of powerful mutagens, heterocyclic amines, which are carcinogenic to the target organs in animal models. Fish-eating populations have lower incidences of heart disease and of many types of cancers than do other populations, which may be the result of the n-3 polyunsaturated oils found in fish. Among other dietary practices that may reduce the risk of cancer and cardiovascular disease are consuming 5-9 servings of fruits and vegetables daily, which provides antioxidants such as quercetin and isothiocyanates; having a high fiber intake, including bran cereal; and drinking 1.5-2.5 L of fluids daily. Tea polyphenols found in black and green tea may have a protective effect against heart disease and some cancers. Concentrates of such desirable products have been made available in pill form to complement health-promoting personal lifestyles. Biomedical research funded by The National Institutes of Health and organizations such as the American Cancer Society has produced sound results that could lead to prevention of chronic disease. The public must heed this information to achieve long-term health.
Return to top ↑

43 Weisburger JH. Lifestyle, health and disease prevention: the underlying mechanisms. Eur J Cancer Prev. 2002 Aug;11 Suppl 2:S1-S7.

International studies in geographic pathology provide background information that a disease may have a quite different incidence and resulting mortality as a function of area of residence. Investigations in animals can model fairly precisely what is learned through such international research, and provide the basis for examining relevant hypotheses and, more importantly, possible mechanisms of action. These approaches can yield public health recommendations and health promotion activities. Regular intake of foods rich in saturated fats, such as meat and certain dairy products, raises the risk of coronary heart disease, especially in smokers. The total mixed fat intake is associated with a higher incidence of the nutritionally linked cancers (i.e. of the postmenopausal breast, distal colon, prostate, pancreas, ovary and endometrium). Monounsaturated oils, such as olive or canola oil, are low-risk fats, as shown in animal models, and through the finding that the incidence of coronary heart and neoplastic diseases is lower in the Mediterranean region, where such oils are customarily used. Fish and fish oils are protective. The associated genotoxic carcinogens for several of these cancers, and also in heart disease causation, are heterocyclic amines, produced during the broiling and frying of creatinine-containing foods such as meats. Excessive salt intake is associated with high blood pressure and with stomach cancer, especially with inadequate intake of potassium, from fruits and vegetables, and calcium from certain vegetables and low-fat dairy products. Bran cereal fiber intake, especially with adequate calcium, yields an increased stool bulk, eliminating factors involved in colon and breast cancer. Vegetables and fruits, as well as soy products, are rich in antioxidants that are essential to lower disease risk stemming from reactive oxygen species in the body. Green and black tea are excellent sources of such beneficial antioxidants of a polyphenol nature, as are cocoa and chocolates. Antioxidants also extend healthy aging and may protect against Alzheimer's and Parkinson's diseases. Nutritional lifestyles can be described for most populations in the world and offer the possibility of a healthy long life.
Return to top ↑

44 Weisburger JH. Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol. 1999 Sep-Oct;37(9-10):943-8.

Most chronic diseases, including coronary heart disease and many types of cancer depend on the in vivo conversion of cellular macromolecules or of carcinogens to specific reactive, oxidized forms. For that reason, health promoting nutrition involves the daily intake of five to 10 vegetables and fruits, fruit juices, red wine and tea that are rich sources of micronutrients with antioxidant properties, including the antioxidant vitamins C, E and beta-carotene. Tomatoes contain lycopene, a stable, active antioxidant. Many vegetables contain quercetin and related polyphenolic compounds. Tea is a source of epigallocatechin gallate, in green tea, and theaflavin and the associated thearubigins, in black tea. Red wine contains resveratrol. The diverse antioxidants in foods, red wine and tea provide the necessary antioxidant resources for the body to control oxidation reactions in the body with possible adverse consequences. For example, the oxidation of low density lipoprotein (LDL) cholesterol yields a product that damages the vascular system. Thus, a lower intake of saturated fats to decrease the levels of LDL cholesterol, together with an adequate intake of antioxidants, is the optimal approach to lower heart disease risk. Cancer of the stomach involves the consumption of salted, pickled foods yielding direct-acting carcinogens, and their formation is inhibited by vitamins C and E. Cancer in the colon, breast, prostate and pancreas may be caused by a new class of carcinogens, the heterocyclic amines, formed during the broiling or frying of creatinine-containing foods, including fish and meats. Their formation and action can be inhibited by antioxidants such as those in soy, tea, vitamin C and also by the synthetic antioxidants BHA or BHT. The growth, cell proliferation and development of abnormal preneoplastic and neoplastic cells also involves oxidation reactions, including the formation of active oxygen or peroxy compounds. Such reactions can be inhibited by antioxidants, such as those in tea, tomatoes or vegetables. Even ageing and longevity in good health would be favoured by the availability of adequate amounts of varied antioxidants. Prevention of the formation and of action of reactive products by antioxidants as present in fruits, vegetables, tomatoes, red wine and tea is of great public health importance in decreasing the risk of major diseases. Prevention is the optimal approach to disease control, and also as an effective route to lower costs of medical care.
Return to top ↑

45 Weisburger JH. Tea and health: a historical perspective. Cancer Lett. 1997 Mar 19;114(1-2):315-7.

In many parts of the world, green tea and black tea are produced from the plant Camellia sinensis. Tea is one of the most widely consumed beverages, second only to water. It is one of the safest beverages since it is made with boiling, sterile water and has been popular for over 4000 years. Dogma has it that people knew it might have health promoting properties since it was frequently used as fluid supply for patients suffering from infectious diseases. However, detailed, focused research on the health benefits of tea is of recent vintage. Initially, such research was carried out in Japan and China and, because the local customs, this research involved green tea. Now, a number of other scientists in Europe and in the United States have conducted investigations on black tea, and in some laboratories exacting comparative studies were performed utilizing black and green tea. The major interest in tea and health stems from the high level of antioxidant tea polyphenols in green tea and black tea. The chemistry of the tea polyphenols has been worked out to some extent. Thus, their role in lowering the risk of heart disease and of a number of types of cancer begins to be understood. Most productive are multi-disciplinary approaches, considering data from epidemiology and field studies, and laboratory research in animal models for heart disease and cancers of various types, as well as through in vitro experiments.
Return to top ↑

46 Weisburger JH. Tea and health: the underlying mechanisms. Proc Soc Exp Biol Med. 1999 Apr;220(4):271-5.

Detailed multidisciplinary research on the effect of tea and the associated tea polyphenols has led to major advances on the underlying mechanisms. In most studies, green and black tea have similar effects, four of which are reviewed in this paper. 1) Tea polyphenols are powerful antioxidants that may play a role in lowering the oxidation of LDL-cholesterol, with a consequent decreased risk of heart disease, and also diminish the formation of oxidized metabolites of DNA, with an associated lower risk of specific types of cancer. 2) Tea and tea polyphenols selectively induce Phase I and Phase II metabolic enzymes that increase the formation and excretion of detoxified metabolites of carcinogens. 3) Tea lowers the rate of cell replication and thus the growth and development of neoplasms. 4) Tea modifies the intestinal microflora, reducing undesirable bacteria and increasing beneficial bacteria. The accumulated knowledge suggests that regular tea intake by humans might provide an approach to decrease the incidence of and mortality from major chronic diseases.
Return to top ↑

47 Weisburger JH. Worldwide prevention of cancer and other chronic diseases based on knowledge of mechanisms. Mutat Res. 1998 Jun 18;402(1-2):331-7.

International research, particularly as part of US/Japan programs, has led to major advances in knowledge of causes of heart disease, stroke, many types of cancer and diabetes, showing that individual lifestyle is associated with these diseases. In Japan, a major health problem is high blood pressure and stroke, and cancer of the stomach, from excessive use of salt and salted, pickled foods, and the relative low intake of protective fruits and vegetables. We identified a likely gastric carcinogen, 2-chloro-4-methylthiobutanoate, in salted, pickled fish. In the Western world, heart disease and cancer of the breast, colon, rectum, prostate, pancreas, ovary and endometrium relate to a nutritional tradition too high in total fat and fried or broiled meats, and too low in fiber, vegetables and fruits. The cooked meats contain genotoxic chemicals, heterocyclic amines, causative elements in heart disease and the nutritionally linked cancers. Decreasing total fat intake, from 40 to 20% of calories and a greater use of starches such as rice, pasta, potatoes and whole grain bread, as well as daily intake of five to nine vegetables and fruits would be beneficial. Adults should consume 2.5 l of fluids per day. Green or black tea and fruit juices have health promoting properties. Regular exercise contributes to good health, and to the avoidance of obesity, a major problem in the USA and of increasing importance in Japan. Avoidance of a risky lifestyle would likely prevent diseases important not only for the individual and his family, but with major impact in lowering medical care costs. Tobacco and cigarette use, particularly on a Western diet, involve a high risk of heart attacks, and cancers of the lung, pancreas, kidney, urinary bladder, and cervix, accounting for 35% of medical care expenditures.
Return to top ↑

48 Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst. 1993 Jul 7;85(13):1038-49.

Tea is one of the most popular beverages consumed worldwide. The relationship between tea consumption and human cancer incidence is an important concern. This topic has been studied in different populations by many investigators, but no clear-cut conclusion can be drawn. Whereas some studies have shown a protective effect of tea consumption against certain types of cancers, other studies have indicated an opposite effect. Our purpose is to provide a critical review of this topic, covering basic chemistry and biochemical activity of tea, epidemiologic investigations, and laboratory studies, as well as possible directions for future research. Studies have demonstrated either a lack of association between tea consumption and cancer incidence at specific organ sites or inconsistent results. On the other hand, many laboratory studies have demonstrated inhibitory effects of tea preparations and tea polyphenols against tumor formation and growth. This inhibitory activity is believed to be mainly due to the antioxidative and possible antiproliferative effects of polyphenolic compounds in green and black tea. These polyphenolics may also inhibit carcinogenesis by blocking the endogenous formation of N-nitroso compounds, suppressing the activation of carcinogens, and trapping of genotoxic agents. The effect of tea consumption on cancer is likely to depend on the causative factors of the specific cancer. Therefore, a protective effect observed on a certain cancer with a specific population may not be observable with a cancer of a different etiology. On the basis of this concept, we suggest future laboratory and epidemiologic studies to elucidate the relationship between tea consumption and human cancer risk.
Return to top ↑

49 Zhang H, Spitz MR, Tomlinson GE, Schabath MB, Minna JD, Wu X. Modification of lung cancer susceptibility by green tea extract as measured by the comet assay. Cancer Detect Prev. 2002;26(6):411-8.

Green tea is widely consumed throughout the world and is known to possess various beneficial properties that may affect carcinogen metabolism, free radical scavenging, or formation of DNA adducts. Therefore, it is plausible that green tea extract may modify BPDE-induced DNA damage. In this report, we utilized the comet assay to (1) evaluate BPDE-induced DNA damage as a potential marker of cancer susceptibility and (2) assess the ability of green tea to modify BPDE-induced DNA damage. DNA damage in individual comet cells was quantified by (1) visually measuring the proportion of cells exhibiting migration versus those without and (2) the length of damaged DNA migration (comet tail). We detected a dose-response between BDPE concentration and mean comet tail length in EBV-immortalized lymphoblastiod (lymphoid) cell lines. As the concentration of BPDE increased from 0.5 to 3 microM, the length of the mean comet tail length increased proportionally in the 3590P (derived from a healthy subject) and 3640P (derived from a patient with head and neck cancer) cell lines. In separate experiments using lymphoid cells from 21 lung cancer cases and 12 healthy subjects, the mean comet tail length was significantly higher in the lung cancer cases (80.19 +/- 15.55) versus the healthy subjects (59.94 +/- 14.23) (P < 0.01). Similar findings were observed when analyzing the mean percentage of comet induced cells (84.57 +/- 8.85 and 69.04 +/- 12.50, respectively) (P < 0.01). When green tea extract was added in conjunction with BPDE, there was a notable reduction of the mean comet tail length (13.29 +/- 0.97) as compared to BPDE treatment alone (80.19 +/- 15.55) (P < 0.01) in lung cancer cases. There were no statistical differences between the baseline (no treatments) (12.74 +/- 0.63) and the green tea extract treatment (13.06 +/- 0.97) (P = 0.21). These data suggest the modification of lung cancer susceptibility by the green tea extract. Similar results were observed for the percentage of induced comet cells and the statistical trends were similar for the 12 healthy subjects. This preliminary study demonstrated that the detection of BPDE-induced DNA damage via the comet assay may be a useful biologic marker of lung cancer susceptibility. The differential effects in BPDE-induced DNA damage between lung cancer cases and healthy subjects suggests predisposed cancer susceptibility to lung cancer risk. This reports also demonstrated the chemopreventive effects of green tea extract on BPDE-induced DNA damage. These observations provide further support for the application of the comet assay in molecular epidemiologic studies.
Return to top ↑

Fleminger, Inc. • 160 Hawley Lane, Suite 205 • Trumbull, CT 06611
©2004. Fleminger, Inc.