Clarification of the Mechanism of Reduction of
Side Effects in Digestive System of an Anti-Tumor Drug through
Ingestion of Amino Acids Cystine and Theanine
Reported on June 23, 2016 at the 25th Annual Meeting of the
Multinational Association of Supportive Care in Cancer
TOKYO, June 28, 2016 – Ajinomoto Co., Inc. (“Ajinomoto Co.”) is conducting research from bench to bedside with the aim of utilization in clinical practice of cystine and theanine, which are both amino acids (hereafter, “Amino Acids Cystine and Theanine”1). In 2014, a group of medical doctors at Sendai Open Hospital (Takashi Tsuchiya, Director), whose research Ajinomoto Co. had been supporting, confirmed a reduction in side effects in the digestive system, such as diarrhea and stomatitis, caused by an anti-tumor drug as well as significant improvement in the completion rate of anti-tumor drug treatment through ingestion of Amino Acids Cystine and Theanine.* Ajinomoto Co.’s Institute for Innovation has clarified this mechanism and reported the results of its research on June 23, 2016 (local time) at the 25th Annual Meeting of the Multinational Association of Supportive Care in Cancer, the world’s biggest supportive care society for cancer, which was held in Australia.

As a result of advances in oral anti-tumor drugs, in recent years it has become possible to conduct anti-tumor drug treatment without hospitalization, while patients continue their work and daily lives. However, with that method of administration, many anti-tumor drugs cause apoptosis of normal intestinal epithelial cells as well as of tumors (direct effect), thus reducing the intestinal barrier function. The intestinal bacteria that enter the body as a result induce an inflammatory response,2 which is thought to then suppress proliferation and induce apoptosis of intestinal epithelial cells (indirect effect), producing side effects in the digestive system such as diarrhea and stomatitis. This often leads to reduction of dosage or discontinuance of administration of anti-tumor drugs, and thus reducing side effects is an issue in anti-tumor drug treatment.

The research reported by Ajinomoto Co. investigated effects of orally administered Amino Acids Cystine and Theanine in mice in which the administration of fluorouracil (5-FU),3 which is the main component of anti-tumor drug TS-1,4 had caused side effects in the digestive system such as diarrhea. In the intestinal epithelial cells of mice that had not been given Amino Acids Cystine and Theanine, apoptosis due to the anti-tumor drug was observed on the day after administration of 5-FU (direct effect) and apoptosis due to inflammatory response was observed four days after administration (indirect effect). On the other hand, when Amino Acids Cystine and Theanine were given, diarrhea symptoms in the mice improved, similar to the results of the clinical study by Dr. Tsuchiya and his group.* Further, the intestinal epithelia of these mice showed improvements in indirect effects due to inflammatory response such as apoptosis and suppression of proliferation (reduction of apoptosis/increase of proliferation) without suppressing apoptosis due to the anti-tumor drug (direct effect).

Apoptotic Index of Intestinal Epithelial Cells

This finding that ingestion of Amino Acids Cystine and Theanine suppresses apoptosis of intestinal epithelial cells (indirect effect) when administering an anti-tumor drug suggests the possibility that these amino acids can be widely used for reduction of side effects in the digestive system such as diarrhea. Furthermore, it has been reported that ingestion of Amino Acids Cystine and Theanine increases glutathione,6 which has an in vivo antioxidative effect7 and an immunomodulation effect, thus suppressing inflammatory response.

Ajinomoto Co. will contribute to healthy lives by continuing to conduct amino acid research from bench to bedside to resolve issues in clinical practice.

Supplementary Data
Effect of Administration of Amino Acids Cystine and Theanine to Mice on an Anti-Tumor Drug Induced Diarrhea Model (Diarrhea Score)
In the group to which 5-FU had been administered, the diarrhea score was observed to rise (worsening of diarrhea symptoms) from the sixth to eighth day after administration. On the other hand, in the group to which 5-FU plus Amino Acids Cystine and Theanine had been administered, no rise in the diarrhea score was seen consistently throughout the experiment period, confirming that 5-FU induced diarrhea was suppressed.

(Diarrhea Score)
0: normal, 1: loose stool, 2: loose stool (including some water), 3: diarrhea (solid), 4: diarrhea (watery)

Glossary
1. Amino Acids Cystine and Theanine
1) Cystine is an amino acid found in relatively large amounts in meat. It is formed by a disulfide bond on the sulfhydryl group between molecules of cysteine, a non-essential amino acid.
2) Theanine is an umami amino acid contained in green tea leaves, and is a derivative of glutamate, a non-essential amino acid. Upon ingestion, theanine breaks down into glutamate and ethylamine in the body.
3) Ingestion of Amino Acids Cystine and Theanine has been shown to improve immunosuppression during high-load exercise tests, to suppress cold symptoms and to suppress excessive inflammation after surgery.
2. Inflammatory response
A physiological response that appears in an organism as a result of immune response activity when undergoing external stress such as the entry of bacteria in the body. An excessive or continuing inflammatory response causes an abnormal condition in the immune response, which delays the restoration of tissue.
3. Fluorouracil (5-FU)
A fluoropyrimidine anti-tumor drug that induces apoptosis of cancer cells by inhibiting synthesis of nucleotides. A pharmacologically active drug contained in TS-1.
4. TS-1
An anti-tumor drug used for digestive system cancer (gastric cancer and colorectal cancer), head and neck cancer, non-small cell lung cancer, non-resectable and recurrent breast cancer and pancreatic cancer. Side effects include stomatitis, anorexia, diarrhea and malaise, as shown in Mochizuki et al., Br J Cancer (2012) 106(7) 1268-1273.
5. Crypt
An invagination (small tubular pocket) in the luminal (internal) surface of the small or large intestine. Proliferating cells exist in the crypt with the role of supplying epithelial cells to the luminal surface of the intestine through constant cell division.
6. Glutathione
1) A substance combining the three amino acids glutamate, cysteine and glycine, in that order. An essential in vivo antioxidant. It is sold as a pharmaceutical in Japan.
2) Effect of increasing glutathione production capability
In joint research by Ajinomoto Co. and the Osaka Prefectural Institute of Public Health, oral administration of cysteine and theanine was observed to increase glutathione synthesis, and has further been shown to augment immune function (Kurihara et al., J Vet Med Sci. 2007 69(12) 1263-70; Takagi et al., J Vet Med Sci. 2010 72(2) 157-65).
7. Antioxidative effect
Detoxification of an organism’s oxidative stress. The action of balancing and normalizing conditions where reactive oxygen is produced in large amounts in vivo, creating a barrier to various organelles, or conditions where detoxication of reactive oxygen cannot keep pace with its production.

* Announced at the 52nd Annual Meeting of the Japan Society of Clinical Oncology (August 2014)
http://www.ajinomoto.com/jp/presscenter/press/detail/2014_09_01.html(Japanese only)

About Ajinomoto Co.
Ajinomoto Co. is a global manufacturer of high-quality seasonings, processed foods, beverages, amino acids, pharmaceuticals and specialty chemicals. For many decades Ajinomoto Co. has contributed to food culture and human health through wide-ranging application of amino acid technologies. Today, the company is becoming increasingly involved with solutions for improved food resources, human health and global sustainability. Founded in 1909 and now operating in 27 countries and regions, Ajinomoto Co. had net sales of JPY 1,185.9 billion (USD 9.87 billion) in fiscal 2015. For more about Ajinomoto Co. (TYO: 2802), visit www.ajinomoto.com.

For further information, please contact:
Ajinomoto Co., Inc. Public Communications Department; pr_info@ajinomoto.com
 
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