Effects of platinum-containing drugs on tissue and cellular distribution of trace metal-relaterd proteins

• Project/Area Number: 20K07143
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Osaka Medical and Pharmaceutical University (2021-2022); Osaka University of Pharmaceutical Sciences (2020)
• Principal Investigator: Nakamura Tsutomu 大阪医科薬科大学, 薬学部, 教授 (80379411)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: プラチナ / 癌 / 癌化学療法 / 微量元素

Outline of Research at the Start

鉄、銅、亜鉛といった生体内微量元素（バイオメタル）は生命現象と深く関わっている。申請者はこれまでに、バイオメタルが金属であることに着目し、癌化学療法で汎用されるプラチナ系抗癌薬投与後の影響を患者血液検体を用いて検討してきた。その中で、一部のバイオメタルでは血中動態が変動することを明らかにしてきたが、組織中の変動をどのように反映しているかは不明な点が多い。本研究では、組織レベルでのバイオメタル分布について解析を進めるとともに、プラチナ系抗癌薬がバイオメタルの分布に与える影響をタンパク質レベルで解明し、プラチナ系抗癌薬の副作用発現予測法や予防法への応用を目指す。

Outline of Final Research Achievements

Limited quantities of clinical samples are available. As a pretreatment for efficient measurement of metal elements, the conditions for ashing using a microwave sample digester were investigated, and the treatment conditions were optimized. After platinum-based chemotherapy, it is detected in the body for a long period of time, and it was suggested that its elimination from the blood is related to factors such as albumin, regardless of renal function. In addition to the variation of essential trace metals in the body, the isotope effect was also examined for the same patient samples, and it was found that the isotopic ratios of iron, copper, and zinc in the plasma may differ from the natural ratios. Further studies are required.

Academic Significance and Societal Importance of the Research Achievements

プラチナ系抗癌剤は消化器癌などの固形癌に対して汎用される薬剤である。一方で、プラチナが金属であることから同薬剤を用いる治療によって鉄、銅、亜鉛といった生体に必須の微量金属元素（バイオメタル）に影響する可能性がある。バイオメタルの変動をモニターすることによって生体が受けた影響を定量的に評価できる可能性があり、疾患の診断や治療効果の判定ならびに副作用の発現予測に応用できると考えている。

Research Products

• [Journal Article] Risk Assessment of Neutropenia during Low-Dose Valganciclovir Prophylaxis for Heart Transplant Recipients (2022)
  • Author(s): Mai Otokubo , Kyoichi Wada , Megumi Ikura , Kotoka Hayase , Takaya Uno , Kazuki Nakagita , Naoki Hayakawa , Takuya Watanabe , Osamu Seguchi , Norihide Fukushima , Tsutomu Nakamura
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 4 Pages: 452-459
  • DOI: 10.1248/bpb.b21-00860
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-04-01
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of Medication Guidance Sheets for Patients With Non-Hodgkin’s Lymphoma Receiving ESHAP±R Therapy (2022)
  • Author(s): UCHIDA MAYAKO、MURATA SAEKO、MORIKAWA HANAE、YONEMITSU HIROKO、ISHIDA SHIGERU、SUETSUGU KIMITAKA、TSUJI TOSHIKAZU、WATANABE HIROYUKI、KAWASHIRI TAKEHIRO、KATO KOJI、HOSOHATA KEIKO、MIYAMOTO TOSHIHIRO、EGASHIRA NOBUAKI、NAKAMURA TSUTOMU、AKASHI KOICHI、IEIRI ICHIRO
  • Journal Title: Anticancer Research Volume: 42 Issue: 4 Pages: 2053-2060
  • DOI: 10.21873/anticanres.15686
  • Peer Reviewed
• [Journal Article] Evaluation of Medication Instruction Sheets for Patients Undergoing R-CHOP Therapy in Non-Hodgkin’s Lymphoma (2022)
  • Author(s): UCHIDA MAYAKO、KAWAI RIKA、HISAMITSU RIE、MAI SAYAKA、ISHIDA SHIGERU、WATANABE HIROYUKI、KAWASHIRI TAKEHIRO、KATO KOJI、HOSOHATA KEIKO、MIYAMOTO TOSHIHIRO、EGASHIRA NOBUAKI、NAKAMURA TSUTOMU、AKASHI KOICHI、IEIRI ICHIRO
  • Journal Title: In Vivo Volume: 36 Issue: 3 Pages: 1461-1467
  • DOI: 10.21873/invivo.12852
  • Peer Reviewed
• [Journal Article] Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure (2022)
  • Author(s): Hosoda Hiroshi、Nakamura Tsutomu、Yoshihara Fumiki
  • Journal Title: Biomolecules Volume: 12 Issue: 9 Pages: 1281-1281
  • DOI: 10.3390/biom12091281
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of medication guidance sheets for patients with non-Hodgkin's lymphoma receiving ESHAPA±R therapy. (2022)
  • Author(s): Mayako Uchida, Saeko Murata, Hanae Morikawa, Hiroko Yonemitsu, Shigeru Ishida, Kimitaka Suetsugu, Toshikazu Tsuji, Hiroyuki Watanabe, Takehiro Kawashiri, Koji Kato, Keiko Hosohata, Toshihiro Miyamoto, Nobuaki Egashira, Tsutomu Nakamura, Koichi Akashi, Ichiro Ieiri.
  • Journal Title: Anticancer Res Volume: －
  • Peer Reviewed
• [Journal Article] Evaluation of medication instruction sheets for patients undergoing R-CHOP therapy in non-Hodgkin's lymphoma. (2022)
  • Author(s): Mayako Uchida, Rika Kawai, Rie Hisamitsu, Sayaka Mai, Shigeru Ishida, Hiroyuki Watanabe, Takehiro Kawashiri, Koji Kato, Keiko Hosohata, Toshihiro Miyamoto, Nobuaki Egashira, Tsutomu Nakamura, Koichi Akashi, Ichiro Ieiri.
  • Journal Title: In vivo Volume: －
  • Peer Reviewed
• [Journal Article] Relationship between serum bepridil concentration and corrected QT interval (2021)
  • Author(s): Kazuki Matsui, Yutaro Mukai, Kota Sakakura, Kyoichi Wada, Tsutomu Nakamura, Atsufumi Kawabata, Nobue Terakawa, Naoki Hayakawa, Kengo Kusano, Kouichi Hosomi, Satoshi Yokoyama, Mitsutaka Takada.
  • Journal Title: Int. Journal of Clinical Pharmacology and Therapeutics Volume: 59 Issue: 01 Pages: 63-70
  • DOI: 10.5414/cp203843
  • Peer Reviewed
• [Journal Article] Discontinuation of oral amphotericin B therapy does not influence the pharmacokinetics of tacrolimus in heart transplant patients (2021)
  • Author(s): Megumi Ikura, Tsutomu Nakamura, Takaya Uno, Kazuki Nakagita, Hiromi Takenaka, Sachi Matsuda, Ryosuke Oda, Kyoichi Wada, Yuji Hattori, Osamu Seguchi, Masanobu Yanase, Naoki Hayakawa, Norihide Fukushima.
  • Journal Title: Int. Journal of Clinical Pharmacology and Therapeutics Volume: 59 Issue: 08 Pages: 566-571
  • DOI: 10.5414/cp204005
  • Peer Reviewed
• [Journal Article] Risk Factors for Skin Toxicities Associated with Bendamustine-Based Chemotherapy in Patients with Non-Hodgkin Lymphoma (2020)
  • Author(s): Uchida Mayako、Mori Yasuhiro、Akiba Kenta、Miyasaka Moena、Hirano Tatsuya、Ikesue Hiroaki、Yamaguchi Yuki、Takano Aoi、Maegawa Nami、Shimomura Yoshimitsu、Hosohata Keiko、Muroi Nobuyuki、Ishikawa Takayuki、Hashida Tohru、Nakamura Tsutomu
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 10 Pages: 1577-1582
  • DOI: 10.1248/bpb.b20-00428
  • NAID: 130007920938
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-10-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk Factors for Febrile Neutropenia Induced by Docetaxel Chemotherapy in Patients with Non-small Cell Lung Cancer (2020)
  • Author(s): Uchida Mayako、Yamaguchi Yuki、Hosomi Syuhei、Ikesue Hiroaki、Mori Yasuhiro、Maegawa Nami、Takano Aoi、Sato Yuki、Hosohata Keiko、Muroi Nobuyuki、Tomii Keisuke、Hashida Tohru、Nakamura Tsutomu
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 8 Pages: 1235-1240
  • DOI: 10.1248/bpb.b20-00266
  • NAID: 130007883886
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-08-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between dexamethasone treatment and alterations in serum concentrations of trace metals. (2020)
  • Author(s): Kazuhiko Yamashita, Takashi Ogihara, Maho Hayashi, Takayuki Nakagawa, Yuma Ishizaki, Manabu Kume, Ikuko Yano, Riho Niigata, Jun Hiraoka, Hiroyuki Yasui, Tsutomu Nakamura.
  • Journal Title: Pharmazie Volume: 75 Pages: 218-222
  • Peer Reviewed