Dietary foods and fruits possess an array of flavonoids with unique chemical structure and diverse bioactivities relevant to cancer. Numerous epidemiological studies have validated the inverse relation between the consumption of flavonoids and the risk of cancer. Flavonoids possess cancer blocking and suppressing effects. Flavonoids modulate various CYPs involved in carcinogen activation and scavenging reactive species formed from carcinogens by CYP-mediated reactions. They induce biosynthesis of several CYPs. They are involved in the regulation of enzymes of phase-II responsible for xenobiotic biotransformation and colon microflora. Since cytochromes P450, P-gp and phase-II enzymes are involved in the metabolism of drugs and in the processes of chemical carcinogenesis, interactions of flavonoids with these systems hold great promise for their therapeutic potential. The role of flavonoids also includes the inhibition of activation of pro-carcinogens, inhibition of proliferation of cancer cells, selective death of cancer cells by apoptosis, inhibition of metastasis and angiogenesis, activation of immune response against cancer cells, modulation of the inflammatory cascade and the modulation of drug resistance. This has greatly extended the goal of cancer therapy from eradicating the affected cells to control of the cancer phenotype. Phytotherapy is being used in combination with other therapies as phytonutrients have been shown to work by nutrient synergy.

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Epigallocatechin gallate (EGCG), a main anticancer component in green tea, has a poor bioavailability in rats and humans due to oxidation, metabolism and its efflux. It was hypothesized that nutrients that address these problems might result in increased bioavailability. Plasma concentrations of EGCG at various time intervals were determined to calculate and compare the pharmacokinetic parameters after oral administration of green tea extract (GTE) or GTE as a nutrient mixture (E) or E + quercetin (Q)/red onions. In rat studies, supplementation of GTE with other nutrients (E) or E + Q raised the plasma C(max) from 55.29 +/- 1.70 to 61.94 +/- 1.70 ng/mL and 94.44 +/- 1.59 ng/mL, respectively. The corresponding t((1/2)) elimination was 2.04 +/- 0.2 h, 3.63 +/- 0.66 h and 2.28 +/- 0.049 h. The AUC(0-24h) were 510.16 +/- 9.88 for GTE, 601.72 +/- 19.10 ng.h/mL for E and 794.08 +/- 15.27 ng x h/mL (p < or = 0.05) for E + Q. In human studies when GTE was fed as GTE or E or E + red onions, the C(max) values were 348.4 +/- 76.6, 384.0 +/- 78.5 ng/mL and 468.4 +/- 131.4. AUC(0-8h) was 1784.1 +/- 56.06 (GTE), 1971.5 +/- 566.5 ng x h/mL (E) and 2490 +/- 878.1 (E + Q), but the change in t((1/2)) elimination was not significant.In conclusion, it is possible to increase the bioavailability of EGCG by supplementing it with nutrients and quercetin.

(-)Epigallocatechin-3-gallate (EGCG), a green tea component, has been attributed with anticarcinogenic and antioxidant activities. The extent and rate of absorption of EGCG by the small intestine depends on various factors such as molecular size, lipophilicity, solubility, pKa, gastric and intestinal transit time, lumen pH, membrane permeability and first pass metabolism. The bioavailability of EGCG can be increased by decreasing the presystemic elimination by stabilizing EGCG in the lumen, helping its transfer across the intestinal apical membrane and its accumulation and thus its availability by inhibiting phase I and II enzymes and phase III transporters. In a crossover study, five human volunteers were given a single oral dose of GTE (A), nutrient mixture (NM) containing GTE (B) and formulation B along with black grapes 250 g (C). Blood samples were drawn at 0, 2, 4, 6 and 8 h. The pharmacokinetic parameters were analysed by WinNonLin (Vs 5.0.1.) using a non-compartmental approach. Supplementation with nutrient mixture normally prescribed to cancer patients containing ascorbic acid, selenium, N-acetyl cysteine and other nutrients (formulation B) resulted in an increase of the systemic availability of EGCG by 14% and formulation C further increased it by 13%, thus leading to a total increase of 27%.

Abstract. Mammary tumors were developed by intraperitoneal injection of N-methyl-N-nitrosourea (MNU) in 21-day-old, sexually immature female Wistar rats. Injection of MNU was repeated 14 weeks after the first one. When palpable tumors were evident in all of the rats, various dietary treatments were initiated for a period of 8 weeks. The treatments were designed to provide 30 mg green tea extract either alone or as a nutrient mixture (E). E was then expanded to include either a nutrient supplement (N), quercetin (Q) or both (N+Q). At the end of the treatment, tumor size/rat measured in the live rats was significantly lower in the groups receiving E, E+Q, E+N and E+N+Q than in the positive control (PC) group which did not receive any dietary treatment. Tumor number/ rat, tumor volume/rat and tumor weight/rat were evaluated after sacrificing the rats on the 60th day. The rats receiving E+N+Q showed significantly lower values for the three parameters as compared to the PC group. The PC group showed 24 carcinomas mostly of grade III severity, while the E+N+Q group had only 6 carcinomas, all of which were of grade II severity. IntroductionN-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in female rats is frequently used as an animal model for the investigation of breast carcinogenesis and the treatment of breast cancer in humans (1-12). In our previous studies with MNU-induced rat mammary carcinogenesis, we observed that the specific formulation of nutrient supplements containing ascorbic acid, L-lysine, L-proline, L-arginine, N-acetyl cysteine selenium, copper and manganese along with green tea extract (GTE) fed to the animals reduced the incidence, number and weights of the tumors (12) measured 30 weeks post-MNU. The combination was designated by the authors as 'Nutrient Synergy' (NS) to underscore the synergistic action of various constituents. The beneficial results obtained in the studies were mainly attributed to epigallocatechin-3-gallate (EGCG), the principal anticancer agent present in the GTE in the NS (13,14). Our previous in vitro studies with cancer cell lines demonstrated that an increase in the concentration of EGCG in the cell culture media resulted in increased anticancer activity. These findings suggested that when the plasma levels of EGCG are increased, this increase is reflected in the elevated anticancer activity. Our recent investigation (15) showed that the plasma level of EGCG in rats was elevated by as much as 25% when a small amount of quercetin (Q) was administered along with GTE as a nutrient mixture (E) + nutrient supplement (N). It was therefore hypothesized that the anticancer activity of E is enhanced when Q is fed in combination with E+N.Our previous MNU study (12), based on previous investigations, was conducted for as extensive a period as 30 weeks following the MNU injection. Various studies by Thompson and associates (6,8,16) indicated that the prolonged period of experimentation of such studies can be considerably reduced when MNU is administered to 21-day-old sexually...