Kampo Treatment for Cancer Introduction Kampo Medicine Originated in Ancient China and Developed Uniquely in Japan

[ Special Feature ]

Kampo Treatment for Cancer Introduction Kampo medicine originated in ancient China and developed uniquely in Japan. It has been both taught to, and used by, conventional Western physicians for the last 30 years. Currently, more than 70% of Japanese physicians (including nearly 100% of Japanese obstetrics and gynaecology (Ob/Gyn) doctors) use Kampo medicine in daily practice including the university hospital, together with high-tech medical treatments like organ transplantation or robotic surgery. Kampo medicine is considered a government- regulated prescription drug and currently 148 formulas are listed on the Japanese national insurance program. As for cancer treatment, Kampo medicine is widely used by surgeons and oncologists. It is widely used in the regular practice for the treatment of cancer and cancer-related symptoms from the early stage to the terminal care. Because Kampo medicine has been totally integrated into Western medicine in Japan, motivation to promote clinical trials is Kenji Watanabe lacking. On the contrary, basic research concerning cancer Department of Kampo Medicine treatment have piled over the last 30 years by the physicians Keio University School of Medicine, Tokyo, Japan and pharmaceutical researchers. Prevention of recurrence or metastasis of cancer cells have been well studied in basic research, however there is little data in the clinical study because it takes time to accomplish. In this review article, Kampo treatment for cancer will be medicine originated in ancient described based on the clinical and basic research articles. KampoChina and developed uniquely in Japan. More than 70% of Japanese physicians Prevention of Cancer use Kampo medicine in daily practice. As for Chemoprevention is one of the topics in cancer treatment cancer treatment, Kampo medicine is widely used by surgeons and oncologists. It is used in since it has been reported that non-steroidal anti-inﬂ ammatory the regular practice for the treatment of cancer drugs (NSAIDs) reduce the prevalence of colon cancer. and cancer-related symptoms from the early stage to the terminal care. This paper describes Kampo treatment for cancer, making references to Shosaikoto (小柴胡湯 ) for the prevention of the publications in clinical and basic research. hepatocellular carcinoma Since Shosaikoto was reported to decrease the serum

1186 ■ Volume 11 > Numbers 17 & 18 > 2007 www.asiabiotech.com [ Special Feature ]

al.2 investigated the anti-oxidative levels of tumors in Shosaikoto-treated Kampo medicine actions of Shosaikoto, and found mice were higher than those of that, Shosaikoto inhibited the 8- tumors in untreated mice at benign, is considered a hydroxy-2’- deoxyguanosine (8- malignant, and terminal stages of the government-regulated OHDG) formation, which is a DNA tumors. The reduced Ret expression prescription drug and adduct by reactive oxygen species at the terminal stage was partially and known to be a genetic risk for restored. From this experiment, currently 148 formulas hepatocarcinogenesis. it was concluded that the anti- are listed on the tumor effect of Shosaikoto involves the promoted preparation of Ret Shoseiryuto (小青竜湯) for the Japanese national protein as a tumor transplantation prevention of lung cancer insurance program. antigen, which probably overcomes In the basic research, there are its potentially increased oncogenic several reports. One is the Shoseiryuto activity. levels of AST and ALT, it has been (小青竜湯) for the prevention widely used for the treatment of of lung cancer. Lung cancer was chronic hepatitis. Because chronic induced in the mouse model by 4- Treatment with Surgical hepatitis is very common in Japan nitroquinolone-N-oxide (4NQO) s.c Operation as well as other Asian countries and followed by the glycerol intake. This Daikenchuto (大建中湯) for the no established treatment is available, treatment induced the lung tumor in prevention of post-surgical ileus Shosaikoto is widely used for the 93.3% of mice without Shoseiryuto, Daikenchuto has been shown to purpose of liver protection. Oka et and 33.3% with Shoseiryuto. This data be effective in preventing the post- al.1 reported on a fi ve-year follow- showed the reduction of the onset of surgical ileus and widely used to up study of liver cirrhosis patients. lung cancer with Shoseiryuto. prevent ileus after abdominal surgeries The subjects were 260 patients in the fi eld of not only gastrointestinal and randomly divided into two but also gynecology. Daikenchuto also groups, one treated with Shosaikoto Shosaikoto (小柴胡湯 ) for the prevents post-surgical intestinal and the other without. Onset of prevention of melanoma adhesion by gastroprokinetic and the hepatocellular carcinoma and Another study was done by anti-infl ammatory effects. Motilin, survival rate were evaluated. The Kato et al.3 He established a RET- results revealed that the onset of transgenic mouse line (304/B6) in hepatocellular carcinoma decreased which stepwise development of In the US, the and longevity improved in the group a skin melanocytic benign tumor effectiveness of with Shosaikoto especially in the and malignant melanoma can be Shosaikoto, Hochuekkito group of liver cirrhosis by non-B observed. In this mouse model, viruses. In the US, the effectiveness he demonstrated that the herbal and Ninjinyoueito as of Shosaikoto, Hochuekkito medicine Shosaikoto has anti- well as glycirrhizine are and Ninjinyoueito as well as tumor and anti-metastatic effects glycirrhizine are listed as the effective on malignant melanoma through listed as the effective treatment for the chronic hepatitis. regulation of protein expression treatment for the However the mechanism is not levels of matrix metalloproteinase chronic hepatitis. obvious, it is assumed that oxidative (MMP) and its inhibitor. This study stress plays an important role in was followed by additional evidence hepatocarcinogenesis. Shiota et showing that Ret protein expression

1 Oka, H., Yamamoto, S., Kuroki, T., Harihara, S., Marumo, T., Kim, S.R., Monna, T., Kobayashi, K. and Thango, T. (2002) Prospective stydy of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer 76, 743–749.

2 Shiota, G., Maeta, Y., Mukoyami, T., et al. (2002) Effects of Sho-saiko-to on hepatocarcinogenesis and 8-hydroxy-2’-deoxyguanosine formation. Hepatology 35(5), 1125–1133.

3 Kato, M., Isobe, K., Dai, Y., Liu, W., Takahashi, M. and Nakashima, I. (2005) Further characterization of the Sho-saiko-to-mediated anti-tumor effect on melanoma developed in RET-transgenic mice. J. Invest. Dermatol. 114, 599–601.

www.asiabiotech.com Volume 11 > Numbers 17 & 18 > 2007 ■ 1187 [ Special Feature ]

Steam manipulation is observed in with Juzentaihoto. Daikenchuto has been converting the Gingerol to Shogaol in the ginger and this Shogaol is Saireito (柴苓湯) alleviates the shown to be effective important in secreting CGRP leading side-effects of CDDP in preventing the post- to the increase of blood fl ow of the Another study examined 26 cases of lung cancer, which was surgical ileus and gut as a result. Prolonged paralytic ileus divided into 2 groups, one with widely used to prevent occurring in the hepatectomized Saireito (n = 10) and the other without (n = 16). Nephrotoxicity ileus after abdominal patients may induce hyperammonemia. Daikenchuto is used with cis-diamminedichloroplatinum surgeries in the field to suppress the elevation of serum (CDDP) was evaluated. Serum of not only gastro- ammonia in hepatectomized levels of BUN increased in the group without Saireito, while serum intestinal but also patients. Presumably, Daikenchuto stimulates the peristalsis and does BUN levels were not elevated in the gynecology. not allow the growth of the intestinal group with Saireito. Also, creatinin bacteria producing ammonia. Imazu clearance became lower and N- et al.4 showed this hypothesis acetyl-D-glucosaminidase increased, while those markers stayed as normal one of the neuro-peptides which is with a different Kampo formula, in the group with Saireito. This study a powerful inducer of motor activity Juzentaihoto. He showed that the showed that Saireito is effective in in the gastrointestine, was elevated in change of the intestinal flora is alleviating the nephrotoxicity of the blood after the administration of the main resource of the serum CDDP. Daikenchuto in humans. In addition, ammonia elevation and this is Daikenchuto has been shown to suppressed by Juzentaihoto, because induce production of vasoactive with Juzentaihoto, the change of the Juzentaihoto (十全大捕湯) intestinal peptide (VIP) and 5- intestinal fl ora was suppressed. alleviates the side-effects of CDDP hydroxytryptamine (serotonin) in Sugiyama et al.5,6 screened human plasma. These neuropeptides Treatment with 11 Kampo formulae to evaluate may play a role to induce the Chemotherapy the protection of nephrotoxicity motility of the gastrointestine. Also, There are many reports that induced by CDDP. Among the Sanshol in Zanthoxylum piperitum Kampo treatment reduces the side- 11 Kampo formulae, nine formulae binds to the vaniloid receptor and effects of chemotherapy. Juzentaihoto showed significant reduction of stimulates the peristalsis. [6]-shogaol alleviates the side-effect of UFT nephrotoxicity. Although Flosemide is an important component in dried (Uracil-Tegafur, anti-cancer drug). also reduced the nephrotoxicity, it ginger and produces an increase Six months follow-up study of also diminished the effectiveness of in the gastrointestinal blood fl ow, gastric cancer patients with UFT CDDP. Among nine Kampo formulae which is medicated by calcitonine after curative operation revealed that reduced the nephrotoxicity, gene-related peptide (CGRP), that suppressor T cell function Juzentaihoto was the most effective. and explains why Daikenchuto is was lower and cytotoxic/killer cell Juzentaihoto also protected the liver useful in the treatment of intestinal function higher in the group with and suppressed the liver injury. ischemia-related diseases. This action Juzentaihoto. This study also showed Among the herbs in Juzentaihoto, is observed only when steamed that subjective and objective adverse Angelicae radix showed the most ginger is used and not the dry ginger. symptoms caused by UFT were less effectiveness in liver and kidney

4 Imazu, Y., Tsuiji, K., Toda, T., et al. (2006) Juzentaihoto reduces post-partial hepatectomy hyperammonemia by stabilizing intestinal microbiota. J. Tradit. Med. 23, 208–215. 5 Sugiyama, K., Ueda, H., Suhara, Y., Kajima, Y., Ichio, Y. and Yokota, M. (1993) Protective effects of Kampo medicines against cis-diamminedichloroplatinum (II)-induced nephrotoxicity and bone marrow toxicity in mice. J. Med. Pharm. Soc. 10, 76–85.

6 Sugiyama, K., Ueda, H., Suhara, Y., Kajima, Y., Ichio, Y. and Yokota, M. (1994) Protective effect of sodium L-malate, an active constituent isolated from Angelicae Radix, on cis-diamminedichloroplatinum (II)-induced toxic side effect. Chem. Pharm. Bull. 42, 2565–2568.

1188 ■ Volume 11 > Numbers 17 & 18 > 2007 www.asiabiotech.com [ Special Feature ]

administration. Hangeshashinto is irradiation. Kampo formulae Among the herbs in used to stop the irinotecan-induced were Juzentaihoto (十全大補 diarrhea. Mori et al.7 reported the 湯), Ninjinyoueito (人參養榮湯) Juzentaihoto, Angelicae result of RCT of Hangeshashinto and Hochuekkito (補中益氣湯). radix showed the most and CPT-11. Of the 41 patients Irradiation only survival rate is with advanced lung cancer, 18 took higher in the group treated with effectiveness in liver Hangeshashinto and 23 did not. Kampo formulae. Five- and ten- and kidney protection. Among 41 patients, 39 experienced year survival rates were 65.6% and diarrhea. Although there were no 49.1% in the irradiation only group differences of diarrhea frequency (total number was 119; stage IIb, protection. Sodium malate in and duration, severe diarrhea (grades 64 cases and stage IIIb, 55 cases). On Angelicae radix was responsible 3 and 4) was reduced in the group the other hand, these were 75.6% for protecting the liver and kidney with Hangeshashinto (one among and 65.9% in the irradiation with functions. The mechanism of action 18 patients) as compared to the Kampo group (total number was 82; of sodium malate was that this group without Hangeshashinto (nine stage IIb, 43 cases and stage IIIb, 39 compound binds to CDDP and among 23 patients). This study cases). This study showed that the forms the diammino-platinum(II) showed that Hangeshashinto is combination of Kampo formula and malate, which has a similar chemical recommended for use with CPT-11. irradiation improved the survival structure to the CDDP-derived The mechanism of action is also well rate of progressive uterus cancer chemical, Carboplatin (CBDCA). studied. CPT-11 is changed to 7- patients. This CBDCA is used clinically and ethyl-10 hydroxy-camptotecin (SN- it has less toxicity against the kidney, 38) in the liver and SN-38 undergoes Juzentaihoto for the hematopoiesis however, the effect is weaker. glucronate conjugation changing after irradiation Also, this sodium malate did not into inactive SN-38 glucronide. Effects of Juzentaihoto on the increase bone toxicity; Juzentaihoto Later, it is excreted into the bile, recovery of hemopoietic systems protected the bone marrow and β and is then deconjugated by - from radiation injury are analyzed. blood cell count was not decreased glucronidase, which was contained Colony-forming unit-spleen (CFU-S) with Juzentaihoto. in the intestinal bacteria to become are hematopoietic colonies formed in Hangeshashinto (半夏瀉心湯) SN-38 again. This SN-38 induces the spleen of recipient mice that have alleviates the side-effects delayed diarrhea. Hangeshashinto been lethally irradiated and injected of CPT-11 contains baicalin, which serve as with donor bone marrow cells. β Another good example that another resource of -glucronidase. Day-14 CFU-S represents primitive showed the reduction of the This competitive action of baicalin hematopoietic stem cells (HSCs) side-effects of chemotherapy against SN-38 glucronide inhibited and day-9 CFU-S represents more is Hangeshashinto. Irinotecan the formation of active form of mature HSCs. The mice injected hydrochloride (CPT-11), a semi- SN-38 without glucronide. As a with Juzentaihoto-treated bone synthetic derivative of camptothecin, result, the delayed diarrhea caused by marrow cells showed better general is an anti-cancer drug which deconjugated SN-38 was alleviated condition, heavier spleens with larger inhibits nucleic acid synthesis by by Hangeshashinto. and more numerous colonies than topoisomerase I inhibition. CPT-11 the control mice on day 14. On the possesses a wide anti-tumor spectrum Treatment with Irradiation other hand, there was no difference and is widely used for the treatment There is a report that the in the number of CFU-S between of lung cancer, colon cancer and irradiation with Kampo improved Juzentaihoto-treated and control malignant lymphoma. Diarrhea is the survival rate in the progressive groups on day 9. Since the day-14 the main side-effect that occurs uterus cervical cancer. Treatment CFU-S assay is thought to reﬂ ect the in the early stage and causes was the combination of low dose most primitive progenitor cells in the the discontinuation of the drug in situ irradiation and external hematopoietic system, these results

7 Mori, K., Kondo, T., Kamiyama, Y., Kano, Y. and Tominaga, K. (2003) Preventive effect of Kampo medicine (Hangeshashin-to) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer. Cancer Chemother. Pharmacol. 51(5), 403–406.

www.asiabiotech.com Volume 11 > Numbers 17 & 18 > 2007 ■ 1189 [ Special Feature ] strongly suggested that Juzentaihoto to manage pain experienced by Conclusion acts on stem cells in the G0 phase to terminal cancer patients. However, it I introduced a part of the manifest recovery-enhancing effects induces severe constipation, causing evidences of Kampo medicine for from radiation injury. After this an obvious reduction in quality of the treatment of cancer. As a matter study, the same group fractionated life. Daikenchuto is evaluated in the of fact, Kampo medicine is broadly Juzentaihoto to obtain oleic acid mouse model and has been shown used for the treatment of cancer from and found that linolenic acid in to improve the gastrointestinal the early stage to the end of life care. Juzentaihoto was the responsible movement. The mechanism is Juzentaihoto and Hochuekkito are the compound. assumed to enhance the contraction most commonly used; Juzentaihoto is of longitudinal muscle and relax investigated to a greater extent than Prevention of Recurrence the tonic contraction of circular Hochuekkito. However, we need to and/or Metastasis muscle. This mechanism explains the further investigate the indications This is one of the very interesting mechanism of action of Daikenchuto and mechanism of action and clarify points with Kampo treatment. There for the constipation induced by the usefulness of Kampo treatment are a lot of basic research studies morphine. for cancer. and several clinical studies currently ongoing. The mechanism is also being studied. Biography Kenji Watanabe, MD, PhD, FACP Juzentaihoto for the prevention of colon cancer metastasis PRESENT ACADEMIC RANK AND POSITION Current Position Title: Oral administration of 2001–present Associate Professor Juzentaihoto before tumor inoculation Department of Kampo Medicine resulted in the dose-dependent Keio University School of Medicine inhibition of liver metastasis of EDUCATION colon 26-L5 carcinoma cells and Degrees: signiﬁ cant enhancement of survival 1984 MD, Keio University School of Medicine, Tokyo, Japan 1991 PhD in Immunology, Keio University School of Medicine, Tokyo, Japan rate compared to the untreated control. This effect was lost when Residency: 1984–1986 Internal Medicine, Keio University Hospital, Tokyo, Japan macrophages and T-cells were eliminated. These data support the Fellowship: fact that immunological function 1986–1988 Internal Medicine, Ashikaga Red Cross Hospital, Tochigi, Japan 1988–1991 Endocrinology, Keio University Hospital, Tokyo, Japan plays a central role in the mechanism of Juzentaihoto. Postdoctoral Training: 1991–1993 Department of Genetics, Stanford University, California, USA 1993–1995 Cell and Molecular Biology Laboratory, Life Science Division, Palliative Care SRI International, California, USA Kampo medicine is also used in palliative care. Ninjinto (人參湯), BOARD CERTIFICATION 1987 Japanese Board of Internal Medicine Shikunshito (圓君子湯),Rikkunshito 1989 Japanese Board of Occupational Medicine (六君子湯) and Bukuryoshigyakuto 1989 Japanese Board of Oriental Medicine (茯苓四逆湯) were often used to 2003 Fellow of American College of Physician improve patients’ appetite and help them recover from the cachexia. Contact Details: Dr Kenji Watanabe Address: Department of Kampo Medicine Daikenchuto for the constipation Keio University School of Medicine by morphine 35 Shinanomachi, Shinjuku-ku Tokyo 160-8582, Japan Morphine is the most effective Tel: +81 3 5366 3824 anti-nociceptive agent and is used Fax: +81 3 5366 3825 E-mail: [email protected]

1190 ■ Volume 11 > Numbers 17 & 18 > 2007 www.asiabiotech.com