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Vol. 4, 153-156, January 1998 Modulation Yasuyuki Sadao of Cancer Sadzuka,2 Tomomi Chemotherapy Sugiyama, Sciences, University of Shizuoka, Shizuoka Japan the modulation Biochemical has played in the development of cancer rected our attention to the intake investigated the effects the antitumor combined activity ascites of green in the green tea tumor was green green The out the by the not was green tea combination. tea can improve and been cancer the therapy. would become of in in normal tis- the enhance- may and effective chemotherapy, extensively of antitumor e.g., treatments. enhancement not antitumor enough, as the result of a new modulator, addition, cations the use and adds mor to improve intake activity tumor reduce and there the modulators are some of patients cases side The development antitumor agents, activity has been iments, designed clinical combination widely used The is also In necessary. activity antituanti- modulation will biochemical in part by the this fact. 1 This work was supported in part Research and Education Foundation. requests for reprints Sciences, University Phone: 81-54-264-5610; by a Grant-in-Aid should may tea tea and inhibits the previously. tea is restricted hinder the mental have a bad influence action cancer green on therapy patient’s cancer would mental be- condition tea as usual. the effects In this of drinking study, tea with DOX,3 therapy (10-12), and were we green tea investigated the an antitumor antibiotic on tumor-bearing mice. caffeine, which agents examined AND are known (13-16), to en- as green tea as well. from was (Shizuoka, The highest purity and be addressed, of Shizuoka. 52-1 Fax: 81-54-264-5615. from from was Green purchased tea powder The other drugs chemicals (Adriacin’), Inc. Tokyo Kasei from was was (Tokyo, Co., Japan). Ltd. (Tokyo, Wako Pure Chemical a product of Shizuoka were dissolved used in this in sterile study isotonic were of the available. Male 20-25 CDFJ g, were and BDF1 strain obtained mice, from S weeks Japan of SLC, Inc. (Hamamatsu, Japan). The animals were housed in a room maintamed at 25 ± 1#{176}C with 55 ± 5% relative humidity and were free access to regular chow Tokyo, Japan) and water. Ltd., Tumors. Ehrlich ascites mal) were i.p. transplanted collected on the 7th day was kindly for Cancer pellets carcinoma (MF; Oriental (1 106 into the CDF1 mice. after transplantation. provided X Tokyo, cells/ani- The ascites were M5076 ovarian by Dr. T. Tashiro Research, Co., (Japanese Foun- Japan). Animal Experiments. Ehrlich cells/animal) were transplanted ascites onto carcinoma the backs (5 X of CDF1 mice. DOX (2.0 mg/kg/day the 10th, 12th, 14th, and for 4 days) was i.p. administered on 16th days after transplantation. Green tea powder for 4 days) (1.0 gfkg/day and theanine and caffeine Shizuoka at School Yada, 10 mg/vial Fermentation, purchased Animals. age injection, Kyowa Japan). saline. METHODS DOX Japan). Caffeine Industries, Ltd. io5 payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to To whom been green (5-9), investigated a positive of antitumor (5), purchased given enhances the improved Received 5/20/97; revised 9/5/97; accepted 10/10/97. The costs of publication of this article were defrayed Pharmaceutical 422, Japan. has of the oral administration of green we have performed animal exper- to consider of theanine the sarcoma 2 Green or black that that treatment. components dation indicate has by drinking of green in clinical effects hance and needed. the number of mcdiSimultaneously, the of life of patients of its the of enhances this type burden. induce examination of food or beverage as modulator (biochemical modulation), then activity by the patient’s tea and better during Theanine in the of modulators increases to the patient’s burden. the quality of the activity modulation. of antitumor has been (3, 4), are confirmed when effects, which the side effects If the the enhancements of biochemical reduces study and modulation 5-fluorouracil However, of are dying tea (Ca- that patients. biochemical (1-4), drugs, been coffee, expect To examine the effects tea on cancer chemotherapy, Chemicals. In cancer tea, we could effects increase never green If green chemotherapy, more chemotherapy of life of clinical on come concen- have MATERIALS effects is high. for clinical patients. These restrictions stability of the patients and/or occasionally INTRODUCTION clinical green beverages evaluations drinking admin- combination Furthermore, encourage the quality studied to Japanese common China for a long time. Some reported to have useful effects chemotherapy Frequently, oral the observed cancer on Ehr- ment of antitumor activity of doxorubicm induced by green tea was observed in M5076 ovarian sarcoma, which has low sensitivity to doxorubicin. These results suggest that drinking our attention of the in these tea the inhibitory In contrast, concentration after on The doxorubicin increased doxorubicin. and We carried 2.5-fold di- beverages mice. growth. role have tea components and tumor-bearing tea enhanced with doxorubicin sues of doxorubicin. on tumor We of common tea and of doxorubicin carcinoma of doxorubicin an important chemotherapy. of green treatment tration one interest 153 Research carcinogenesis and is known to be effective for the chemoprevention of cancer (8, 9). However, the effects of green tea on ABSTRACT istration directed sinensis), popular in Japan components have Cancer Tea’ We have mellia of Pharmaceutical lich by Green and Hirota School 422, Clinical of Shizuoka 3 The abbreviation used is: DOX, doxorubicin. Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer Research. 154 Green Tea Enhances Cancer Chemotherapy 120 100 100 80 80 ,. E 60 60 . C) a) 40 -S 0 E 0 20 F- 20 0 0 Control p. DOX 0 o. i. p. + Caffeine DOX . DOX #{247} Green Tea DOX Theanine + DOX . DOX p. Green + Tea DOX + p. i. 0. DOX Theanine Caffeine + Fig. I Effects of green tea and tea components on the changes in tumor weight (Ehrlich) induced by DOX. Each column is the mean of eight mice expressed as percentage of control level; bars, SD. Significant differences from the level of the DOX-alone group are indicated by: a) P < 0.001; b) P < 0.01; and c) P < 0.05. Fig. 2 Effects of test drug on the DOX concentration in the tumors of mice. Each point is the mean of eight mice; bars, SD. Significant difference from the level of the DOX-alone group is indicated by: a) P < 0.001. (100 DOX mg/kg/day 13th, 15th, days) of tea mice were tissues for and killed of 10 mM or on the 18th and the the the 1 lth, mg/kg/day for same solid day. 4 (pH 7.8); ovarian sarcoma planted onto the backs 4 days) was i.p. days after the x (1 of BDF1 administered theanine and (P tumors then DOX was (w/v) 106 cells/animal) 14th, Green 18th, powder mg/kg/day mg/kg/day 16th, (100 20th were p.o. weighed. bearing Mice. jection of DOX with the control with DOX 0.05) and of Green Activity Tea and of DOX Tea Components in Ehrlich Ascites on the Carcinoma growth. enhanced antitumor difference from istration ity of treatment tumor The by DOX to 37% the DOX of theanine DOX of DOX weight alone and group, caffeine (P 2.1-fold < concentrations and green tea of control P enhanced 0.01) and in the tumors < significantly level 0.001). the (significant Oral 1.9-fold, < 0.001). caffeine Similarly, increased the oral DOX administration concentration of by in Fig. theanine 2.2-fold 2. Table DOX 1 . Green concentrations tea, theanine, in the heart and caffeine and liver (P are shown in combination of in the heart Theamne on the Ovarian Sarcoma the tumor of control of green to 37% 2.5-fold evidence and Antitumor Tumor- weight 3. The incompared combined to 55% (P < level. tea was of the control level the DOX inhibitory provides activity were tumor was indicated to be green tea or tea components with alone group. of DOX with regarded as the activity, induced ous reports (13, direct 14), cause by green we the tea acts have of as effect DOX by DOX i.p. Thus, proof the and oral theanine biochemical of green as the in combination of the compared with enhancement that the DOX in the tumor of tea or tea components. confirmed tea concentration concentration the as tea in the tumor, The increased < mor DOX. concentration and was green effective tissues. significantly tea causes the of green tea is by the with that components. the DOX increment that observed or caffeine and in normal This DOX and significantly effect on tumor may expect that green Similarly, the enhancement it is suggested was with Tumor growth of DOX alone green effect the possibility of DOX and tissue, that drinking agents. This We of theanine depends on these We determined the in combined by 25% compared with the control of green tea remarkably reduced the modulator. chemotherapy. caffeine targeted 0.001). The reduced (P < 0.01) administration modulators, Green tea combined with DOX increased the DOX concentration in the tumor by 1.7-fold compared to the DOX-alone group (P significantly 37% a biochemical motes cancer and activ- respectively. are shown concentrations Tumor weights are shown in Fig. alone did not reduce the tumor weight level, whereas green tea and theanine administration admin- antitumor and M5076 This result indicates activity of antitumor g). the in decreased the tumor weight level, whereas the addition new combined and combination treatment on Ehrlich solid tumor-bearing mice. was inhibited by DOX, and the administration Tumor-bearing Mice. Tumor weights after treatment are shown in Fig. 1 . The injection of DOX alone reduced the tumor weight by 25% compared with the control level (0.675 ± 0.108 The Tea DOX tumor weight enhanced by RESULTS reduced of Green of Oral on the 15th, 17th, 19th, and 21st day. The mice on the 22nd day, and solid tumors were rapidly Effects the DOX the DISCUSSION administered were killed Antitumor in the heart particular, 0.05). < mg/kg/day for 4 days) reduced concentration In for and and and (10 tea (2.0 trans- for 4 days) removed theanine DOX the were mice. and DOX Activity extracted the DOX tumor-bearing Effects in 10 volumes mice. on transplantation. of The by chboroform:methanol (4: 1 , v/v). The DOX concentration was determined with fluorescence spectrophotometer (excitation wavelength, 470 nm; emission wavelength, 585 nm). M5076 did not increase liver weighed. homogenized buffer on (10 on day, and were phosphate administered injections performed removed samples p.o. i.p. were rapidly tissue was days, components were The 4 days) 17th antitu- In previtheanine Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer Research. and Clinical Table Doxorubicin 1 con centration Group Each a (ng/g tissue)” Heart alone + green tea + theanine + caffeine value 464 376 224 456 I 12 ± 144 702 618 658 716 ± ± 69h ± ± 232 ± 166 P from the . C) ± 65 ,T 60 a) a) 22 ± mice. level of the DOX alone 40 E group: F- 0.05. < b) 80 0 difference 155 100 Liver 152 ± SD of eight is the mean b Significant Research in the heart and liver of mice DOX DOX DOX DOX DOX Cancer 20 0 caffeine then inhibit the DOX increase causing the the enhanced the antitumor increased increment in normal in by green The vivo. dependent concentration on in the components in green of DOX as well. concentration tea, was theanine, of DOX due in the tumor centration to specifically trations in reduced by the combination suggest that the point normal only. green tea of drug Cardiac reported heart tissues (12, associated reduce hand, the side 18). severe by the heart Because green catechins effect tea has 19-21), (5, of a decrease and in the past side study effects can beneficial effects of antitumor in consideration an ideal combination that data apy. In green is antioxidative expect peroxide level modulation that in the were not per- the antitumor effects green tea described in this the antitumor of drinking in the Thus, we can expect toxicity induced by modulator green and of both whereas Because of DOX because activity and side tea is a common tea with effects chemotherapy is easy to try for humans in clinical treatment. We expect that cancer chemotherapy with the addition of green tea will induce a positive effect. Furthermore, tea, we examined which has M5076 tumor DOX effects sensitivity growth alone. theanine, 55% low to investigate these with of control DOX level. the broad on M5076 to DOX. was In contrast, not observed Thus, The results of green sarcoma inhibitory effect of green the tumor against to Ehrlich which DOX ascites was not carcinoma. effective, On the M5076 an antitumor green a meal. Green chemotherapy. favors a patient’s efficiency the appears demonstrated physiological of effects in clinical drinking as influences on cancer beverage attitude and a treatment green tea of a favorite encourages the and that this efficacy of life in cancer important to effects intake index, the quality chemother- positive mental of the chemotheraputic discovery in the field is chemotherapy. of study of bio- modulation. The fact moprevention may this study the future. drink have that positive in improving This will think of suggest the side as well. For patients it is easy to suggest tea may We was to reduce tea has results on cancer tea and tumors green but also We green tea is useful news be helpful hope that clinicians to these only the for clinical to promote tea, according more not for encouraging be good may be that the patients. cancer che- of chemoThe eradication encourage results, for efficacy their results of of cancer in patients to so that cancer therapy successful. I. Konishi, T., and Dezuki, Y. Biochemical modulation. CRC Crit. of 2. Hidalgo, 0. F., Gonzalez, F., Gil, A., Campbell, W., Barrajon, E. and Lacave, A. J. I 20 hours simultaneous infusion of cisplatin and fluorouracil in metastatic breast cancer. Am. J. Clin. Oncol., 12: 397-401, 1989. weight as to that green tumor, effect that These without similar tea against effect green activity tea, expect Rev., tea enhanced the antitumor activity of DOX against M5076 tumor, indicating that the effects of green tea as a modulator are not specific found important biochemical modulator with antitumor agents, with by green tumors. drinking green may on tea, as well demonstrate study, of we REFERENCES (22), by the administration decreased these usefulness ovarian the combination significantly We addition Therefore, effects the antitumor DOX. the DOX. or drug-resistant this therapy beverage, of tea has a very chemical it has with dose of antitumor green from peroxide could observed the useful biochemical on both agents. was enhancement were These some we in the lipid of a drug, be DOX elevating bow sensitivity concen- of DOX of lipid as well as the DOX concentration. Many studies about biochemical formed con- effects DOX. effects side elevation + Fig. 3 Effects of green tea and theanine on the changes in tumor weight (M5076) induced by DOX. Each column is the mean of eight mice expressed as percentage of control level; bars, SD. Significant differences from the level of the DOX-alone group are indicated by: a) P < 0.01; and b) P < 0.05. enhance is very e.g., because DOX DOX side tea with green tea reduces the lipid peroxide level. that drinking green tea reduces the cardiac DOX the with of green may toxicity 17, other Tea not distribution. to be caused components, the DOX Theanine i- or caffeine. increasing On DOX Green thereby in mainly DOX DOX and vitro tumor, tea and theanine decreased the DOX concentration in the Thus, green tea was shown to enhance the antitumor activity the the activity in DOX tissues cells in it is possible that other on the antitumor effect In contrast, Green heart. Ehrlich tea is considered that tumor. 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To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from clincancerres.aacrjournals.org on May 14, 2017. © 1998 American Association for Cancer Research.