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Carcinogenesis, Vol. 21, No. 5, 915-919, May 2000
© 2000 Oxford University Press

Molecular Epidemiology and Cancer Prevention

(–)-Epigallocatechin gallate can prevent cisplatin-induced lung tumorigenesis in A/J mice

Junko Mimoto, Katsuyuki Kiura3, Keisuke Matsuo2, Tadashi Yoshino1, Ichiro Takata, Hiroshi Ueoka, Mikio Kataoka and Mine Harada

Second Department of Medicine,
1 Second Department of Pathology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558 and
2 Department of Medicine, Okayama Red Cross General Hospital, Okayama 700-8607, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Risks of secondary lung cancer in patients with non-small cell lung cancer and small cell lung cancer are estimated to be 1–2% and 2–10% per patient per year, respectively. Cisplatin is widely used in the treatment of lung cancer and is also known as a carcinogen in experimental animals. In this study, the effect of (–)-epigallocatechin gallate (EGCG) on cisplatin-induced lung tumors in A/J mice was investigated. Female A/J mice (4 weeks old) were divided into four groups: group 1, control without treatment; group 2, EGCG treatment (1 mg/ml in tap water); group 3, weekly cisplatin treatment (1.62 mg/kg body wt, i.p.) for 10 weeks; group 4, cisplatin plus EGCG treatment (EGCG was started 2 weeks before cisplatin treatment). Four groups of mice were killed at week 30 after treatment. Tumor incidence was 26.3% (5/19) in group 1, 30% (6/20) in group 2, 100% (19/19) in group 3 and 94.4% (17/18) in group 4. Tumor multiplicity (the number of tumors per mouse, mean ± SD) was 0.4 ± 0.8 in group 1, 0.4 ± 0.8 in group 2, 5.1 ± 2.1 in group 3 and 2.8 ± 2.3 in group 4. Tumor multiplicity was significantly reduced by adding EGCG to cisplatin-treated mice (P < 0.01). Furthermore, EGCG significantly reduced cisplatin-induced weight loss from 24.7–26.3% (cisplatin treatment) to 10.8–11.6% (cisplatin plus EGCG treatment) (P < 0.01). These findings suggest that EGCG can inhibit cisplatin-induced weight loss and lung tumorigenesis in A/J mice.

Abbreviations: EGCG, (–)-epigallocatechin gallate; JCRB, Japanese Cancer Research Resources Bank; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Green tea contains a variety of polyphenols known as cathechins. (–)-Epigallocatechin gallate (EGCG) is a major component of polyphenols in green tea. Polyphenols in green tea have anti-oxidative (1,2), anti-mutagenic (3,4), anti-carcinogenic (5) and antitumor (6) activities in experimental animals. Epidemiological studies have shown a lower risk of cancer among people who consume a large amount of green tea (7,8).

The global incidence of lung cancer is increasing at a rate of 0.5% per year and, as a consequence, lung cancer is a leading cause of cancer mortality in most countries (9). The introduction of combined modality therapy (chest radiotherapy and cisplatin-based chemotherapy) has produced disease-free long-term survival in lung cancer (10,11). Second primary cancers have increased in small-cell lung cancer (12). The risk of secondary lung cancer in patients with non-small cell lung cancer is estimated to be ~1–2% per patient per year (13). For patients with small-cell lung cancer, the risk is increased to >2–10% per patient per year 10 years after the initial treatment (13). Continued smoking, chemotherapy and chest radiation affect the incidence of secondary lung cancer. These factors will be critical in the prevention of secondary lung cancer. Since free platinum intercalates or intracalates in DNA, cisplatin can be cytotoxic towards lung cancer cells, but it can also enhance carcinogenicity in experimental animals (14). EGCG can prevent 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis; it does this by inhibiting the formation of O6-methylguanine adducts caused by NNK (15) and protecting from oxidative damage through inhibition of 8-hydroxydeoxyguanosine (16), and also has a direct antitumor effect (6). Accordingly, we presumed that EGCG might protect from cisplatin-induced DNA damage and/or inhibit tumor growth directly, and tested whether EGCG could prevent cisplatin-induced tumorigenesis in a mouse model.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals and chemicals
A total of 132 female A/J mice (Japan SLC, Shizuoka, Japan), 4 weeks old and weighing approximately 17 g, were used. The animals were housed, five per plastic cage, and were given free access to tap water and standard laboratory food (MF; Oriental Yeast, Tokyo, Japan). They were kept in an air-conditioned room with 55 ± 10% humidity under a daily cycle of alternating 12 h periods of light and darkness in the Animal Center for Medical Research, Okayama University Medical School. Oriental Menthol Industry (Okayama, Japan) and Nippon Kayaku (Tokyo, Japan) kindly provided EGCG (>75% purity) and cisplatin, respectively. NNK and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were purchased from Toronto Research Chemicals (Ontario, Canada) and Sigma (St Louis, MO, USA), respectively. EGCG was provided in drinking water when indicated in the experiment.

Experimental design
Experiment 1.
Fifty mice were divided into two groups, for treatment with NNK (n = 25) or with NNK and EGCG (n = 25). From 1 week after starting EGCG treatment (1 mg/ml in tap water), mice were treated with NNK (1 mg/kg body wt, i.p.) twice a week for 28 weeks. All mice were killed at week 30 and the number of lung tumors per mouse was determined.

Experiment 2.
Eighty-two mice were divided into four groups as controls (group 1; no treatment; n = 20) or for treatment with EGCG (group 2; n = 20), cisplatin (group 3; n = 22) or cisplatin and EGCG (group 4; n = 20). After 2 weeks of EGCG treatment, mice were treated with cisplatin (1.62 mg/kg body wt, i.p.) once a week for 10 weeks. At week 30 (18 weeks after the last cisplatin treatment), all mice were killed and the number of lung tumors per mouse was determined.

Cell culture and cytotoxicity test
The two non-small cell lung cancer cell lines A549 (JCRB0076) and LK-2 (JCRB0829) were provided by the Japanese Cancer Research Resources Bank (JCRB, Tokyo, Japan). The small-cell lung cancer cell line SBC-3 (JCRB0818) was established in our laboratory (17). The growth medium was RPMI-1640 supplemented with 10% fetal bovine serum, penicillin-G (100 U/ml) and streptomycin (100 µg/mg). Cytotoxicity was evaluated by an MTT assay, which was modified from the original method reported by Mosmann (18), as described previously (17,19). Yang et al. have reported that the maximum plasma concentration (Cmax) of EGCG in humans is 0.326 µg/ml (0.71 µM) and showed that saturation occurs (20). Since <=1 µg/ml EGCG did not affect the absorbance at 560 nm in an MTT assay, EGCG at concentrations of 0.5 µg/ml was used, either alone or in combination with various concentrations of cisplatin.

Statistical analysis
Tumor incidence results were analyzed by the {chi}2 test, whereas data on tumor multiplicity were analyzed by Student's t-test using Microsoft Excel 97 SR-1.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Tumor incidence was 90.9% (20/22) in the NNK group but only 29.2% (7/24) in the group treated with NNK and EGCG (Table IGo). In the mice treated with NNK, 4.6 ± 2.4 (mean ± SD) lung tumors were found per mouse, whereas in NNK-treated mice that drank EGCG in drinking water, there were only 0.6 ± 1.1 tumors per mouse (P < 0.001). After week 12, the mice in the NNK group weighed significantly less than those treated with NNK and EGCG group (Figure 1Go). Three of the 25 mice in the NNK group died (one each at weeks 16, 24 and 24). One of 25 mice in the NNK plus EGCG group died (at week 12). The primary causes of death were not investigated.


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  		Table I. The inhibitory effects of EGCG on gross tumor incidence and multiplicity in A/J mice
 


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  		Fig. 1. Effects of EGCG (1 mg/ml in tap water) on body weight of A/J mice treated with NNK or not treated. Statistical significance (determined by Student's t-test): *P < 0.01; **P < 0.001. Error bars indicate standard errors. NNK (1 mg/kg body wt) was injected intraperitoneally into female A/J mice twice a week for 28 weeks.

 
Table IIGo shows tumor incidence and multiplicity in each group. Tumor incidence was 100% (19/19) and 94.4% (17/18) in groups 3 (cisplatin treatment) and in 4 (cisplatin plus EGCG treatment), respectively. Thus, EGCG treatment did not reduce tumor incidence. However, in mice treated with cisplatin, 5.1 ± 2.1 (mean ± SD) lung tumors developed per mouse, compared with only 2.8 ± 2.3 per mouse in those treated with cisplatin and EGCG. Therefore, EGCG significantly reduced the number of cisplatin-induced lung tumors in A/J mice (P < 0.01). There were no differences in tumor incidence and multiplicity between groups 2 (EGCG treatment) and 1 (control). EGCG alone did not reduce the incidence or multiplicity of spontaneous lung tumors in A/J mice.


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  		Table II. The inhibitory effects of cisplatin on gross tumor incidence and multiplicity in A/J mice
 
Pulmonary tumors were well demarcated and neoplastic cells proliferated with cord-like and/or papillotubular structures (Figure 2AGo). A higher magnification revealed that tumor cells had polygonal cytoplasm with nuclei of various shapes and sizes. Mitotic figures were easily observed (Figure 2BGo). These tumors were classified as an adenocarcinoma according to the description of Yang et al. (21). Some smaller tumors were composed of cells with rather lower anaplasia, which corresponded to adenoma.



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  		Fig. 2. (A) A representative tumor is well circumscribed and composed of cord-like structures with scattering tubules (hematoxylin and eosin stain x300). (B) A higher magnification of panel A. Tumor cells have dysplastic nuclei of various shapes and sizes. Mitotic figures are indicated with white arrowheads (hematoxylin and eosin stain x600).

 
Treatment with EGCG alone did not lead to significant weight gain compared with controls. Mice in group 3 (cisplatin treatment) began to lose significant weight (compared with the controls) 2 weeks after starting cisplatin treatment (P < 0.05 at week 2; P < 0.01 at weeks 4, 6 and 8), but mice in group 4 (treated with cisplatin and EGCG) did not lose weight during the 10 week period after administration of cisplatin. As shown in Figure 3Go, EGCG significantly prevented weight loss in mice treated with cisplatin after week 16. One of 20 mice in the control group died (week 29), two of 20 mice in the group treated with cisplatin and EGCG died (weeks 4 and 23) and three of 22 mice treated with cisplatin died (one at week 23 and two at week 29). The primary causes of death were not investigated, but one mouse in the group treated with cisplatin and EGCG died just after the cisplatin injection.



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  		Fig. 3. Effects of EGCG (1 mg/ml in tap water) on body weight of A/J mice treated with cisplatin or not treated. Statistical significance (determined by Student's t-test): *P < 0.01; **P < 0.001. Error bars indicate standard errors. Arrows indicate intraperitoneal injection of cisplatin (1.62 mg/kg body wt) into female A/J mice.

 
As shown in Figure 4Go, EGCG alone at a clinically achievable concentration did not affect the cytotoxicity of cisplatin on three cell lines of lung cancer in vitro.



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  		Fig. 4. Effect of cisplatin with or without EGCG on SBC-3 (A), A549 (B) and LK-2 (C) cells. Cells (2000 cells/well) were incubated in varying concentrations of cisplatin or in medium with or without EGCG for 96 h. The proportion of surviving cells was evaluated by an MTT assay. {circ}, cisplatin and EGCG (0.5 µg/ml); •; cisplatin only. Data points are the means of two independent experiments; bars represent SD.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
It has been reported that pulmonary adenomas occur in A/J mice 18 weeks after cisplatin treatment (14). Using this system, we demonstrated that tumor multiplicity was significantly reduced by administering EGCG to cisplatin-treated mice (P < 0.01). EGCG induces G2–M arrest and inhibits growth of tumor cell lines (22). It also inhibits production of urokinase, which can decrease tumor size or even produce complete remission of cancer in mice (23). These observations suggest that direct effects of EGCG may contribute to the delay of tumor formation and/or progression. Several experimental studies have demonstrated that green tea polyphenols and/or EGCG can inhibit the incidence of chemically induced tumors in the duodenum (24), colon (25), skin (26,27) and lung (16). We have confirmed that EGCG can inhibit NNK-induced lung tumorigenesis in A/J mice. NNK in cigarette smoke is a potent carcinogen (28), which is related to both secondary and primary lung cancer (29). Cisplatin used in the chemotherapy of lung cancer is also a potent carcinogen (14), which is probably related to secondary lung cancer. We confirmed that EGCG has a chemopreventive effect on NNK-induced tumors and demonstrated a partial effect of EGCG on cisplatin-induced tumors. EGCG thus appears to be a good candidate for chemoprevention of secondary lung cancer.

EGCG decreased both tumor incidence and multiplicity in NNK-induced tumors, whereas it only affected multiplicity in cisplatin-induced tumors. It may act by metabolic inactivation of NNK as well as by direct inhibition of tumor growth. An activated K-ras gene with a specific transition (GGT to GAT) in codon 12, which is generated through the formation of O6-methylguanine adducts by NNK, is frequently detected in NNK-induced lung tumors (30). EGCG can inhibit the formation of O6-methylguanine adducts (15) and thus prevent lung tumors related to an activated ras gene. Although the mechanism of cisplatin-induced tumorigenesis in A/J mice is not well established, EGCG may not inactivate cisplatin directly like NNK in the first stage in carcinogenesis, because EGCG did not reduce the antitumor activity of cisplatin in vitro. EGCG may inhibit tumor growth directly rather than protect from cisplatin-induced DNA damage.

EGCG prevented only additional tumors induced by cisplatin; it did not prevent spontaneous lung tumors.

Belinsky et al. have reported that cisplatin reduces NNK-induced cancer multiplicity (31). In their experiment, cisplatin treatment was initiated 42 weeks after NNK treatment. At this time point, adenocarcinoma of the lung induced by NNK already exists and can be treated by cisplatin. Furthermore, mice were killed after 8 weeks of cisplatin treatment. This follow-up period is too short to detect carcinogenicity of cisplatin. In their system, the effects of cisplatin as an anticancer drug could overcome its effects as a carcinogen.

In the first experiment, NNK (1 mg/kg body wt) was injected intraperitoneally into female A/J mice twice a week for 28 weeks. Low-dose multiple injections of NNK for 28 weeks induced a high tumor incidence (90.9%) with a mean of 4.6 tumors in the lungs. Although the incidence and multiplicity are low when compared with the previous report (16), low-dose, long-term exposure of NNK is closer to the clinical condition, since NNK is a carcinogen in tobacco smoke. EGCG effectively inactivated low-dose NNK and thus markedly reduced both incidence and multiplicity of lung tumors to the background level in A/J mice. Although cachexia-related cytokines, such as tumor necrosis factor and interleukins 1 and 6 (32), were not checked after week 12, significant weight loss in the NNK treatment group during this phase may have been related to NNK-induced tumors themselves rather than the direct NNK toxicity.

EGCG prevented cisplatin-induced weight loss during early and late phases. In the late phase (after week 16), EGCG delayed tumor progression and, as a consequence, might have prevented tumor-related weight loss, as observed in the NNK treatment group. In the early phase of cisplatin administration, EGCG reduced weight loss due to cisplatin's toxicity. EGCG may protect normal cells in the mice from adverse effects of cisplatin, because the mice did not have tumors in this phase. It is not clear why mice treated with cisplatin and EGCG did not lose weight.

Green tea, which contains EGCG, is a natural product and has no harmful effects. However, a large amount of green tea may have minor adverse effects such as epigastric discomfort and sleeplessness caused by caffeine. For clinical application, it is necessary to reduce the adverse effects and to amplify the chemopreventive effect (33). Iwata (34) has reported that purified EGCG is too expensive to be mass produced. For clinical use, crude green tea extract can be produced easily and cheaply. Decaffeinated green tea extract will be useful for reducing adverse effects in clinical application (34).

In conclusion, EGCG partially inhibited cisplatin-induced lung tumorigenesis and weight loss in A/J mice. Our observations suggest that EGCG may prevent the secondary malignancy and weight loss caused by cisplatin and/or tumors themselves.


   Acknowledgments
 
We thank Drs Tadashi Tsuchida, Hiromichi Yamane, Naoyuki Nogami and Akio Hiraki for their excellent technical assistance and helpful suggestions.


   Notes
 
3 To whom correspondence should be addressed E-mail: kkiura{at}hospital.okayama-u.ac.jp Back


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received June 7, 1999; revised December 16, 1999; accepted December 17, 1999.


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