March 26, 2024 TOPICS

[Ambitious Graduate Students] A consistent focus on the side effects of drugs: Working to control the side effects of anticancer drugs on the small intestine

Shizuka Jonan (a fourth-year doctoral student in the Major in Pharmacy at the Graduate School of Pharmacy)

Drugs carry the risk of side effects. Side effects are present in a wide variety of pharmaceuticals, from antihistamines that relieve hay fever symptoms and pain relievers readily available at drug stores to anticancer drugs used in cancer treatment. Shizuka Jonan, a fourth-year doctoral student in the Major in Pharmacy at the Graduate School of Pharmacy, has been searching for novel treatments that address the side effects of drugs. She has continuously addressed the risks and benefits of drugs by focusing her research on the damage to the small intestine caused by anticancer drugs.

The small intestine: A mysterious digestive organ

In Japan, one in two people will get cancer and one in three will die from it. Anticancer drugs play a major role in many of these cancer treatments. In step with recent medical advances, a wide range of anticancer drugs have been developed, and the lives of many patients have been saved. On the other hand, it is also true that anticancer drugs can be accompanied by various side effects.
When the topic of the side effects of anticancer drugs arises, many of us may think of nausea, vomiting, hair loss, and a weakened immune system. In her research, Jonan zeroed in on the damage that anticancer drugs cause to the mucus membranes in the small intestine. The small intestine is considered an important organ for the absorption of nutrients, but surprisingly, diseases of the small intestine have not been fully understood until recently.

“The small intestine is more difficult to examine than other parts of the digestive tract because of its elongated shape and its location inside the body. In recent years, however, advances in technology like capsule endoscopy and double-balloon endoscopy have led to a better understanding of previously unidentified small intestinal diseases, and new perspectives have opened up.
In this context, I focused on glutamate, a safe amino acid that can be consumed daily. When I administered glutamate to mice one week before the administration of anticancer drugs, I observed that damage to the small intestine could be reduced by a certain degree.”

Intestinal roll (Swiss roll) sections from the duodenum (inner small intestine) to the ileum (outer small intestine) of a lab mouse (C57BL/6N) with hematoxylin & eosin stain. A normal section can reach a total length of 30 cm or more.

Glutamate: The key to elucidating mechanisms and developing novel treatments

Jonan conducted an experiment using an anticancer drug called 5-fluorouracil (5-FU). One side effect of cytotoxic anticancer drugs like 5-FU is that they shorten the length of the villi in the mucus membranes of the intestine and the destroy the cellular structure of crypts (tubular indentations in the villi), thereby reducing the intestinal barrier against bacteria and toxins. This results in side effects such as severe diarrhea and weight loss, and greatly impairs the quality of life (QOL) of patients with cancer.

In her experiment, Jonan first administered 5-FU to mice to create a model of drug-induced enteritis, a condition that mimics small intestinal damage. She also prepared another group of mice that received glutamate before 5-FU was administered. During the experiment, Jonan recorded the mice's weight and fecal condition daily, and then she removed ileum tissue from the mice and conducted histological and biochemical evaluations of the tissue condition.
What she found was that the mucus membranes of the small intestine of mice treated with glutamate demonstrated cell structures that were less damaged than in the group not treated with glutamate.

“My experiment demonstrated the efficacy of glutamate, but I believe that going forward, we will need to rigorously examine the detailed mechanism of how glutamate works in the small intestine, using mice and cultured cells. Also, when treating patients with anticancer drugs, one very important factor is how quickly the body can recover and treatment can be resumed after you stop administering drugs temporarily. To this end, I focused on observing tissues and measuring body functions to elucidate the phenomenon of intestinal inflammation caused by anticancer drugs. I hope the results of my research will lead to the development of new treatments.”

By getting to the bottom of the essential question of why glutamate is effective against inflammation caused by anticancer drugs, Jonan is conducting research that goes beyond just elucidating the underlying mechanism and includes the patient approach.

A spirit of inquiry born from an international joint research project in high school

A major catalyst that spurred Jonan’s interest in research was an international joint research project with an overseas sister school that she participated in when she was a student at Ritsumeikan Senior High School. For the first three years of high school, she worked with students from a sister school in Taiwan to research butterfly habitat expansion in a project entitled “Adaptive Strategy of Argyreus hyperbius.” Since then, her fascination with research has grown because she experienced the excitement of pursuing inquiry in a global environment, where discoveries generate new questions. She says this experience still lives on to this day.

“I think the experience of approaching discussions with overseas students with a sense of urgency, where I had to summarize my arguments succinctly in a limited amount of time, has proven beneficial in my current research life. This also led me to start thinking about things with an international perspective, which broadened my horizons. In the lab, I work with a research fellow from Egypt on a joint research project, and we have even published a paper together.”

Jonan decided to go to university to explore pharmacy, a field she has been interested in since she was a child. What inspired her to pursue research on side effects in graduate school was witnessing people close to her suffering from the side effects of cancer. During her practical training at a hospital, she saw a pharmacist proposing measures to one of his cancer patients on how to deal with the side effects they were suffering from, and this made her keenly aware of the importance of assessing drugs for their side effects. Furthermore, her practical training at a medical facility overseas made her realize that side effects are a common issue throughout the world.
Wanting to play an active role in the world, Jonan thought that she could contribute to more people by researching the causes of side effects, so she decided to join Professor Kikuko Amagase's laboratory, which studies gastrointestinal disorders and other side effects of anticancer drugs. According to Jonan, she landed on her current research topic by combining the evaluation of anticancer drug efficacy, which she studied as an undergraduate, with the responsibilities of pharmacists, which she witnessed first-hand during her practical training.

Examining all the possibilities to realize clinical applications

Precisely because her research deals with the evaluation of side effects, Jonan says it is always important to consider whether overcoming those side effects will have an impact on the primary effect of a drug. What’s more, when viewed from a clinical perspective, there is a need to consider the possibility that what is effective in one organ, the small intestine, could cause problems in other parts of the body, such as the heart, liver, or brain. Jonan has a strong desire to not only elucidate functions but also to apply her findings to clinical practice, and she says this is what makes the research interesting even when it raises vexing issues.

“The side effects of anticancer drugs on the small intestine can lead to normal cells failing to multiply properly and dying. On the other hand, if the cells in question are cancer cells, this can be beneficial because their growth can be inhibited. Glutamate, the amino acid that I am researching, is also a neurotoxic agent. This is what makes it particularly difficult to conduct research focused primarily on side effects. Although I run into difficulties because changing your perspective can lead to a different interpretation of the data, I enjoy working on this research because it is rewarding.”

Jonan says she has struggled at times with figuring out what kind of research data she needs to collect and what kind of experiments she needs to run to prove her hypotheses. One thing she makes a point of doing is communicating with researchers and graduate students from a diverse array of fields. During the research phase, when she wanted to analyze the function of a protein, she sought advice from a faculty member passing by, and when she was struggling with the method she was using for genetic manipulation, a faculty member she was introduced to lend her a reference book.

“A single person may be able to conduct an experiment, but I believe that research cannot be accomplished alone. Because there are so many things to consider, I think that consulting directly with specialists in their respective fields is a shortcut to a better understanding. Many of the professors at Ritsumeikan University's Graduate School of Pharmaceutical Sciences/Phamacy are kind and will talk openly with students, even those in other laboratories, thus allowing them to absorb learning from a wide variety of areas. Another attractive feature of our graduate school is that we have a mix of four-year students who aspire to become pharmaceutical researchers and six-year students who pursue their studies with clinical practice in mind. There are many doctors and pharmacists with clinical experience as well as research skills, which creates synergies unique to an environment where people with different backgrounds come together.”

Jonan gives a poster presentation at the World Congress of Basic & Clinical Pharmacology during the fourth year of her doctoral program.

Addressing data, including social trends, and evaluating drugs

Jonan is schedule to work at the Pharmaceuticals and Medical Devices Agency (PMDA) starting in April 2024. PMDA is an organization that aims to improve the health of the people and the level of medical care by reviewing the approval of new drugs, publishing safety information, and providing remedies for side effects and other health problems.

“My job will entail accurately assessing the risks and benefits of drugs and determining, based on scientific evidence, whether or not those drugs should be released to the public, all while responding to social trends. In the future, I would like to contribute to the improvement of drug development around the world by accurately evaluating clinical results received from pharmaceutical companies on a larger scale.”

In her research thus far, Jonan has grappled with how to evaluate research data and how it can be applied to future clinical issues. We will root for her as she continues to explore the future of drug development in a new field.

Related information


March 18, 2024 TOPICS

Reviving Local Small Hydropower Plants