chemoprevention is a novel approach to cancer control using specific natural products or synthetic agents for suppression , reversal , or prevention of premalignant transformation of cells to a malignant form . an ideal chemopreventive agent must have no toxicity , must have high efficacy in multiple sites , should have a low cost , preferred oral consumption , a known mechanism of action , and most important aspect of human acceptance . several studies have shown the natural products , especially antioxidants present in food and beverages have various health benefits with no side effects and toxicity compared to the limitations of other chemotherapeutic agents . natural products are composed of a wide spectrum of biologically active phytochemicals like phenolics , flavonoids , carotenoids , alkaloids , and nitrogen that can suppress the early and late stages of tumorigenesis . the process of carcinogenesis is a multistage process with phases of initiation , promotion , and progression . it is therefore possible to intervene and prevent the process of carcinogenesis during these phases . since it takes several years to reach the invasive stage of an epithelial carcinogenesis ; progression of precancerous lesion can be stabilized , arrested , or reversed by chemoprevention strategies both green tea and black tea have been studied for their chemopreventive potential and green tea has shown greater promise and efficacy against multiple cancers . also , green tea has a ready availability and low toxicity . oral cancer is a heterogeneous group of cancers arising from different parts of the oral cavity with different predisposing factors , prevalence , and treatment outcomes . it is the sixth most common cancer reported globally with an annual incidence of over 300,000 cases and an increase of 62% has been reported in the developing countries . among smokers , the prevalence of oral tumors is 4 - 7 times higher than nonsmokers and if alcohol or chewing tobacco is added to the cigarette usage , the incidence of oral cancer is increased by 19- and 123-folds , respectively . the tobacco carcinogens affect large fields of upper aerodigestive tract mucosa during decades of their usage , causing accumulations of genetic alterations that are involved in tumorigenesis . high incidence of oral cancer in india is attributed to use of tobacco both smoking and chewing and/or alcohol intake . high statistics of the disease and delayed presentation of patients at the time of primary diagnosis of oral cancers ; underscores the need for awareness , early detection , and chemoprevention strategies . in the recent years , infection with human papilloma virus ( hpv ) , particularly hpv 16 has been suggested as an etiologic factor especially among the nonsmokers and nonalcoholics . green tea is derived from the plant camellia sinensis and is mostly consumed next to water . green tea comprises of polyphenols constituting 36% of dry tea leaf weight , glycosides , leucoanthocyanins , and phenolic acid . green tea contains four major polyphenols : epicatechin ( ec ) , epigallocatechin ( egc ) , epicatechin-3-gallate ( ecg ) , epigallocatechin-3-gallate ( egcg ) , composing 1 - 3% , 3 - 6% , 3 - 6% , and 3 - 7% , respectively of the fresh green tea leaf dry weight . the polyphenols found abundantly in green tea have been shown to inhibit a variety of processes associated with cancer cell growth , survival as well as metastasis . several studies have shown benefits of green tea pertaining to its antiviral , antiinflammatory , and antiallergic effects . protective effects of green tea intake against cancer incidence have been shown by a large population - based prospective cohort study . this kind of epidemiology study has spurred intense basic science research of green tea and its components . the implications on the anticancer activity are reported to be on important enzymes like urokinase . ornithine decarboxylase , nadph - cytochrome p450 reductase , protein kinase c , steroid 5-alpha reductase , tumor necrosis factor expression , and nitric oxide synthase . anticancer effects through pathways of antiangiogenesis and inhibition of telomerase have also been shown previously . the egcg and other polyphenols have clearly shown effects on tumor signaling pathways [ figure 1 ] . studies have shown egcg binding to a number of proteins like laminin , vimentin , fas , and insulin - like growth factor 1 receptor . it also has indirect effects on epidermal growth factor receptors ( egfr ) , signal transducers and activators of transcription ( stats ) , and activator protein-1 ( ap1 ) . egcg is also a potent inhibitor of nuclear factor kappa - light - chain - enhancer of activated b cells ( nf-b ) pathways . . 1 = epigallocatechin-3-gallate ( egcg ) modulates the mitogen - activated protein kinase ( mapk ) pathway bringing about growth inhibition . 2 3 = cell cycle arrest by egcg . 4 = promotion of apoptosis by inhibition of bcl2 and bcl - xl green tea polyphenols can induce cell cycle arrest or apoptosis by activating p53 and its targets p21 and bax . studies show that egcg induces apoptosis by activating p73 dependent expression of a subset of p53 target genes including p21 , cyclin g1 , mouse double minute ( mdm ) 2 , wig1 , and pig1 . the target genes that are negatively regulated by egcg include bcl2 , bcl - xl , cyclin d1 , matrix metalloproteinases ( mmps ) , and vascular endothelial growth factor ( vegf ) . previous studies show that green tea polyphenols can inhibit the angiogenesis of breast cancer cells by inhibiting the expression of vegf and mmp9 through stat3 . evidences show that egcg treatment inhibits phosphorylation of egfr tyrosine kinase in head and neck cancer . several studies have shown egcg mediated inhibition of receptor tyrosine kinases such as her2 , her3 , insulin like growth factor-1 receptor ( igf-1r ) , and vegfr and their downstream effectors such as pakt and perk . laminin receptor is identified as a potential receptor for egcg to modulate several important intracellular signaling pathways . previously oral cancer chemoprevention clinical trials have utilized local delivery strategies with several classes of compounds such as vitamin a derivatives , adenoviruses , cancer chemotherapy agents , cyclooxygenase ( cox ) 2 inhibitors , and natural products . the pioneering study using retinoids by sporn et al . showed chemoprevention in the mainstream cancer research . landmark studies showed that high dose 13-cis - retinoic acid ( 13cra ) treatment could reduce the size of precancerous lesions in 67% of patients compared to 10% of the placebo group . evidences show a follow - up phase iii trial of high dose 13cra induction followed by low dose cra being superior to -carotene in maintenance of the premalignant lesions . another phase iii trial using high dose 13cra showed significant reduction in the incidence of primary tumors after 1-year treatment period and lasting for a total of 3 years . a combination of high dose 13cra , -interferon , and vitamin e has been shown to be effective in delaying head and neck associated with second primary tumors and recurrence . high dose 13cra has been found active against oral premalignant lesions but has been found too toxic for long - term administration . subsequent efforts to extend early high dose promise and reduce toxicity by lowering the dosage , failed to reduce the incidence of head and neck cancers . evaluation of the topical fenretinide application in patients with oral leukoplakia / lichen planus ( 100 mg bid for 2 months ) showed regression of premalignant leukoplakia with no adverse side effects and minimal drug levels in the serum . the first clinical trial using green tea for oral premalignant lesions was a double - blind , placebo - controlled , randomized trial in patients with oral leukoplakia having 760 mg of mixed tea capsules along with mixed tea ointment topically vs placebo with topical glycerin . these findings correlated with low egfr positive cells in the treatment group . to evaluate the maximum tolerated dose of green tea , the phase i trial showed dosage of total catechins = 26.9 , egcg = 13.2 , egc = 8.3 , ecg = 3.3 , ec = 2.2 , and caffeine contents = 6.8 with a green tea extract ( gte ) dose of either once or thrice for 4 weeks up to a maximum of 6 months being ideal . the dose limiting toxicities reported were tremors , cough , constipation , and headache ; attributed to the caffeine components of gte . oral gte dose of 1 gm / m thrice daily for at least 6 months was recommended . this study showed that applying tea extracts directly to the lesions may help in improving the local concentrations of the active constituents . the pathological results showed significant decrease in the number and total volume of the silver - stained nucleolar organizer regions and the proliferation cell nuclear antigen in oral mucosa of the treated group compared to the control group . another study showed promising results assigning patients with high risk oral premalignant lesions randomly to receive 3 doses of gte ( 500 , 750 , 100 mg / m ) vs placebo thrice a day for 12 weeks and evaluated the biomarkers in the baseline and 12-week biopsied tissues . this study showed a greater clinical response with the 750 and 1000 mg / m gte ( 58.5% ) and 500 mg / m ( 36.4% ) vs the placebo arm ( 18.2% ) suggesting a good dose - response effect of gte in the oral premalignant lesions . an important biomarker inference from this data showed decreasing vegf expression consistent with previous study . this study showed downregulation of stromal vegf and cyclin d1 in lesions of clinically responsive patients ( gte patients ) and upregulated in nonresponsive patients . this study not only supported the use of gte in chemoprevention of oral premalignant lesions but also use of relevant biomarkers in clinical trials to monitor the response . the only way to ascertain the mechanism of action of the chemopreventive agent at the molecular level towards a response and resistance is by using relevant biomarkers . a natural compound like green tea is well - tolerated and highly consumed and is known to be nontoxic and would not require a phase i trial that evaluates the dose limiting toxicity and determination of maximum tolerated dose endpoints . previous studies have shown synergistic growth inhibitory effects with curcumin in head and neck cancer cell lines . topical curcumin and oral intake of gte have shown superior antitumor effects in 7,12 , dimethylbenzanthracene - induced cancers in vivo . among the many natural compounds , green tea polyphenols and in particular , the results from the completed studies support a potential role of green tea for oral cancer prevention . it is proved by research for more than a decade that green tea polyphenols influences a number of pathways that are relevant to tumor growth proliferation and metastasis . the need of the hour for chemoprevention using green tea is development and validation of biomarkers that can be evaluated by clinical trials in a clinical setting . moreover , if these biomarkers specifically target different stages of carcinogenesis like initiation , promotion , or metastasized ; they will be more useful . oral cancer has been shown to be very suitable for chemoprevention trials because of the precancers being readily accessible for clinical and histopathological examination . oral tumors , due to the process of field cancerization are more prone to second primary tumors and therefore , have a good endpoint in clinical trials . polyphenols modulate some critical targets including p53 , p21 , p27 , p16 , p18 , cyclin d1 , and cyclin e along with cyclin - dependent kinase ( cdk ) 2 , cdk4 , cdk6 , cox-2 , mdm2 , igf - i , igf binding protein ( igfbp3 ) , and nf-b . green tea can therefore be evaluated as a monotherapy given for a longer period of time or in combination with targeted agents . the synergism that has been reported earlier may be helpful in a clinical setting including an oral cancer screening program .