Winner of the 28th Journal of Pharmacological Sciences Outstanding Paper Award (Tomoka Miyamoto, Assistant Professor, Clinical Pharmacy School of Pharmacy)

Department of Pharmacology

Estrogen decline is a risk factor for paclitaxel-induced peripheral neuropathy: Clinical evidence supported by a preclinical study

Assistant Professor Tomoka Miyamoto Clinical Pharmacy School of Pharmacy

In this study, we conducted a clinical retrospective study of female cancer patients and basic experiments using mice to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, breast cancer patients had a higher incidence of PIPN than non-breast cancer patients, and a subanalysis of breast cancer patients revealed that age 57 years or older and endocrine therapy before the start of paclitaxel treatment were associated with severe PIPN. In the basic study, ovariectomy exacerbated PIPN in mice, but this effect was suppressed by repeated administration of 17β-estradiol. Repeated administration of thrombomodulin α (TMα), which is known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in ovariectomized mice. In summary, breast cancer survivors, especially those undergoing postmenopausal estrogen reduction or endocrine therapy, are considered to be a subpopulation susceptible to developing PIPN, and non-hormonal Department of Pharmacology interventions against PIPN are needed, and TMα may be a major candidate for such interventions.

Paclitaxel has a broad range of antitumor activity and is currently used by many patients. However, this drug frequently induces peripheral neuropathy in a dose-dependent manner, significantly reducing the patient's quality of life. The onset of paclitaxel-induced peripheral neuropathy varies from person to person, but it is difficult to predict and there are no preventive drugs. Therefore, elucidating the risk factors for paclitaxel-induced peripheral neuropathy and establishing an appropriate administration schedule of anticancer drugs according to the individual's risk of developing peripheral neuropathy are extremely important issues for continued anticancer treatment.

In this study, we conducted a retrospective study of female cancer patients and basic experiments using mice to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, we analyzed 131 outpatients undergoing chemotherapy containing paclitaxel to investigate the incidence of PIPN. As a result, the incidence of PIPN was significantly higher in breast cancer patients (n = 40) than in non-breast cancer patients (n = 91). In a subanalysis of breast cancer patients, age 57 years or older and endocrine therapy before the start of paclitaxel administration were significantly associated with severe PIPN (CTCAE grades 2 to 4). In the basic experiment, paclitaxel was repeatedly administered to ovariectomized female mice, and mechanical nociceptive thresholds were evaluated using the von Frey test. Ovariectomy worsened PIPN in mice, but this effect was suppressed by repeated administration of 17β-estradiol. Repeated administration of thrombomodulin α (TMα), known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in ovariectomized mice.

In clinical studies, we explore the factors through which estrogen and thrombomodulin affect paclitaxel-induced peripheral neuropathy.

JSPS KAKENHI (26460710/17K09046)

*1 Paclitaxel: A type of anticancer drug that is said to be applicable to various cancers, including uterine cancer, breast cancer, ovarian cancer, and stomach cancer.
*2 Retrospective study: A type of observational study used to investigate the relationship between disease factors and onset. It is also called a "retrospective study" because it collects information on subjects retrospectively from the time the survey began.
*3 17β-estradiol: The most powerful natural estrogen for humans and many mammals. It is secreted from ovarian follicles and is known to affect cell differentiation and proliferation, and exerts its effects by binding to estrogen receptors α (ERα) and β (ERβ).
*4 Thrombomodulin α (TMα) Thrombomodulin is a high-affinity thrombin receptor that is mainly present in vascular endothelial cells, and mucosal epithelial cells of the respiratory tract and intestinal tract. Thrombomodulin α was successfully produced by genetic engineering in an attempt to make a soluble molecule from only the extracellular portion containing the active site of thrombomodulin.