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Research and development of alpha-lipoic acid derivatives which inhibit anticancer medication-induced alopecia

"A large number of researchers participating in the "Research Group on Cancer, Inflammation and Alpha-Lipoic Acid" as well as Oita University Faculty of Medicine work together to conduct research on alpha-lipoic acid derivatives and develop a new drug under the belief of "If it is possible to prevent anticancer medication-induced alopecia, the attitudes of patients with breast cancer facing cancer treatment will change". It is Professor Masafumi Inomata who plays a central role in this effort.

As the birthrate is declining and the proportion of elderly people is growing in Japan, the number of cancer patients is increasing. The optimal treatment for cancer patients is surgery. “Endoscopic surgery is conducted based on the four pillars, curability, safety, minimally-invasiveness (lower burden) and functional preservation” said Professor Masafumi Inomata. He is the person who plays a central role in Oita University Faculty of Medicine and proceeds with research and development of alpha-lipoic acid derivatives.

Translational research incorporating aspects of both basic science and clinical medicine

Are you a leader in the basic medicine although you are a surgeon?

We found that there was a huge problem in conducting cancer treatment as a surgeon in clinical practice although it had not gained much attention.

It used to be thought that even though cancer treatment imposed a tremendous physical burden or caused loss of progressive organ function, it could not be helped because it was a treatment for cancer. It was regarded as acceptable as long as a cancer was cured by surgery. In order to treat a cancer, it would be much better if you could conduct a treatment which imposes as lower physical burden as possible, gives better postoperative patient QOL (Quality of Life) and can preserve organ functions.

Thus, clinicians communicating with patients in clinical practice need to give feedback on problems to basic science, i.e., where the problem lies in and how it should be dealt with. Then, basic researchers are supposed to verify how much invasiveness (physical burden) can be decreased, how organ functions can be preserved or how the body’s immune responds to the treatment and give feedback to clinical medicine. This is now called as translational research. This concept is summarized by the phrase “bench-to-bedside”. Bench refers to basic medicine which verifies ranging from in vitro experiments to animal studies. Based on the results, clinicians give their patients optimal treatment.

It is a collaboration between basic medicine and clinical medicine, isn’t it?

This type of collaboration is important for future medicine. General hospitals cannot do so easily, but university hospitals can deal with both basic medicine and clinical medicine. Oita University was quick to build a collaborative relationship between basic medicine and clinical medicine and has addressed the problems.

You focused on the anticancermedication induced alopecia which had so far been given up and was regarded as acceptable.

Anticancer drugs have greatly improved for the last 25 years. As molecular targeted drugs which attack proteins on the surface of cancer cells or cancerspecific genes have emerged, cancer survival rates have been improving and cancer recurrence can be prevented to some extent thanks to the efficacy of these drugs. A multidisciplinary approach combining surgical treatment with chemotherapy or radiotherapy contributes to improvement in cancer treatment results. Thus, surgeons involving in cancer therapy are required to have knowledge on anticancer agents.

Research and development of alpha-lipoic acid derivatives which prevent anticancer medication-induced alopecia

What inspired you to start research on prevention of anticancer medicationinduced alopecia?

The most common side effect of anticancer agents includes hematologic toxicities such as a decrease in the number of white blood cells and a decline in platelet counts. This is the most important one. If it lowers too much, it can be life threatening. The second one is gastrointestinal symptoms. If dehydration occurs, it could be life threatening. Peripheral neuropathy may also occur. Numbness and tingling in your hands may occur, interfering with your daily life. What arises at the end is alopecia.

Anticancer-medication induced alopecia does not interfere with daily life and is not life threatening. Thus, alopecia has not been paid attention in the 20 to 30year history of anticancer drugs from the medical view point. This is why hair will grow again in 6 months or 1 year after stopping the use of anticancer drugs. “It is OK only when it occurs while doing chemotherapy, isn’t it?” which used to be an attitude of clinicians. Regarding adverse drug reaction, there are international criteria, based on which adverse drug reactions (ADRs) are evaluated. ADRs are reported by grade (level of severity) on a scale of 1 to 5. Alopecia is assessed as grade 2, if the entire scalp may be involved (alopecia totalis), which is regarded as very mild. Grade 5 corresponds to death. Grade 4 corresponds to serious complications. 1 includes almost no subjective symptoms. If mild cytopenia occurs, it is rated as grade 2. In case of moderate cytopenia, it is rated as grade 3 or 4. In contrast, for alopecia, even if all hairs have fallen out, it is rated as 2.

I understand that anticancer medication- induced alopecia has a tremendous psychological burden on women.

To tell you the truth, ADRs are evaluated on whether it is life threatening or not. On the other hand, when I communicate with patients, there are almost none who refuses treatment with anticancer drugs due to a decrease in the number of white blood cells which they are unaware of, while there are many patients who refuse it because of psychological damage saying, “I cannot accept it because it influences how I look”. In addition, anticancer medication-induced alopecia has also substantial damage to the skin. It causes the scalp to become red and painful or to smart. However, adverse effects such as alopecia or skin damage have not been paid attention because it is not life threatening. So, research on anticancer medication-induced alopecia has not so far progressed.

Research on alpha-lipoic acid derivatives

Could you tell me what the mechanism behind anticancer medication-induced alopecia is like?

Alopecia can be divided into two broad types: androgenic alopecia and anticancer medication-induced alopecia. Regarding androgenic alopecia, many researchers including Professor Satoshi Itami of Osaka University have been engaged in the research of the condition. It has been elucidated that the condition is caused by the influence of androgenic hormone and some medications for androgenic alopecia are available.

In contrast, research on anticancer medication-induced alopecia has not made much progress and thus its cause has not been elucidated although patients with the condition are in need for the treatment. Then, we started research on how anticancer medication-induced alopecia is caused together with clinical teams and basic science researchers of Oita University.

Firstly, we developed an animal model with anticancer medication-induced alopecia. Practically speaking, when an anticancer drug is injected into rat abdominal cavity, the hair falls out from the whole body. Then, we observed the conditions of hair loss and investigated what occurred histopathologically with a microscope.

Inflammation occurred mainly in hair matrix cells in hair root leading to fibrosis around these cells. The study result shows that when an anticancer drug reaches the skin through the blood stream, it is most likely to damage hair root, hair matrix cells and dermal papilla cells causing inflammation. More importantly, what a cell dies a natural death is called as apoptosis and we have found that when hair matrix cells are treated with an anticancer drug, they die earlier because of accelerated apoptosis. In addition, as skin changes caused by anticancer medication- induced alopecia, oxidation process in hair matrix cells and their surrounding tissues is accelerated leading to further inflammation-induced apoptosis. We have elucidated these mechanisms and published it in a certain journal.

Then, we thought that inhibiting these three actions might suppress hair loss and thus when administering an alphalipoic acid derivative with potent antioxidant properties we developed into rat abdominal cavity by injection, the alphalipoic acid derivative was delivered to the whole body leading to the suppressed hair loss successfully. However, as the drug is delivered to the whole body, it may cause any adverse effect. Next, we made the alpha-lipoic acid derivative in the form of a cream and applied it to the rat skin. Then, the similar effects were observed. The study results showed that the drug could reach the target area only by applying the derivative to the skin surface because it targeted on the skin where inflammation would occur.

Based on these study results, we developed a hair lotion containing alpha-lipoic acid derivative because we thought that this formulation would cause no adverse effect but would exert a definite effect.

Skin changes of rat model with anticancer medication-induced alopecia

Skin changes of rat model with anticancer medication-induced alopecia

Apoptosis and antioxidant properties

What people are involved in this research and development?

We asked experts in the fields of pharmacology, hair, dosage form design, basic medicine, clinical medicine and anticancer medication as well as Oita University Faculty of Medicine using the CIA Research Group network to take part in this study. It took us three years to start a clinical study after we obtained basic data.

We gave a presentation on this study result at the 7th Annual Conference of the Organization for Oncology and Translational Research in Hong Kong for the first time in 2011. As a drug for inhibiting anticancer medication-induced alopecia was the world’s first one, many people showed strong interest in this study.

Cancer patients have so far received treatthe society and receive cancer treatment paying attention to their QOL. I believe that medical science should support that far and anticancer medication-induced alopecia is one of major challenges to be solved. The breast has become the leading cancer site in female cancer incidence. The incidence of breast cancer in women peaks in their forties. Women in their forties play an active role both at home and in society. In case of breast cancer, anticancer drugs may be given before surgery. Even after the caner is removed, anticancer medications are used for the purpose of recurrence prevention. A substantial proportion of patients with breast cancer use anticancer medications. Given that anticancer drugs give psychological damage to them, we need to do something.

Now that breast cancer awareness has increasingly heightened; landmarks in the world are lit up in pink on the Pink Ribbon Day in October. In response to this heightened awareness, it is an era when healthcare professionals need not only to give treatment to patients but also to consider patient needs and QOL.

Application of alpha-lipoic acid derivative to androgenic alopecia

Do you think that alpha-lipoic acid derivatives are also effective for androgenic alopecia?

The mechanism behind androgenic alopecia differs from anticancer medication-induced alopecia. Androgenic alopecia is caused by the influence of androgenic hormone. First, a drug for inhibiting androgenic hormone which promotes hair loss is needed. We need to conduct research on what effects alpha-lipoic acid derivatives have on androgenic hormone. Taking into account that anticancer medications can suppress apoptosis, we think that they will exert the similar effects. Moreover, whether the derivatives can inhibit 5-alpha reductase, the enzyme, is what we need to investigate next.

Could you tell me the schedule from now on?

We are now conducting a clinical study in which 103 patients with anticancer medication-induced alopecia take part. We plan to have third parties evaluate treatment effects and then perform a joint research with dermatologists in order to proceed with research on the assessment of effects on androgenic alopecia. This is the next strategy, that is, to build a body of evidence for androgenic alopecia. Now, we are ready to start a new product development on hair or hair care products at any time with Aderans.

Interviewer/writer: Akiyoshi Sato Photographer: Naoyuki Tamura

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