@article{oai:repo.qst.go.jp:00076169,
 author = {Matsumoto, Hiroki and Yoshii, Yukie and Baden, Atsumi and Kaneko, Emi and Hashimoto, Hiroki and Suzuki, Hisashi and Kawamura, Kazunori and Ming-Rong, Zhang and Higashi, Tatsuya and Kurihara, Hiroaki and Matsumoto, Hiroki and Yoshii, Yukie and Suzuki, Hisashi and Kawamura, Kazunori and Ming-Rong, Zhang and Higashi, Tatsuya},
 issue = {9},
 journal = {Translational oncology},
 month = {Jun},
 note = {Hypoxia plays important roles in the prognosis of malignant brain tumors such as glioblastoma because it causes drug delivery deficiencies and the induction of hypoxia-inducible factor-1α in tumor cells. Extensive hypoxic areas are associated with poor prognosis of these fatal diseases. We previously reported that multiple administrations of the hypoxia-targeted internal radiotherapy agent Cu-diacetyl-bis(N-methylthiosemicarbazone) (Cu-ATSM), four times at intervals of 1 or 2 weeks, show antitumor effects in glioblastoma without treatment-related adverse events. Before initiating clinical trials, preclinical safety studies using Cu-ATSM composed of stable isotopes and its precursor ATSM were required to understand the potential risks of systemic and repeated chemical exposure of our investigational drug. In this study, the concentrations of Cu-ATSM and ATSM in mouse plasma after intravenous administration were determined by liquid chromatography-tandem mass spectrometry, and the half-lives were estimated to be 21.5 and 22.4 minutes for Cu-ATSM and ATSM, respectively. Based on this result, approach 2 of the current ICH M3 [R2] guideline was adopted, and a 7-day intravenous toxicity study was conducted in mice. Cu-ATSM and ATSM in a ratio of 2:25 mimicking our current investigational drug was used, and no adverse effects were observed when Cu-ATSM and ATSM were administered at 81 μg/kg. These results and those of previous studies suggest that our current investigational drug formulation containing Cu-ATSM and ATSM at a dose of 15 μg can be safely administered to patients once per week for 4 weeks for treatment with Cu-ATSM.},
 pages = {1206--1212},
 title = {Preclinical Pharmacokinetic and Safety Studies of Copper-Diacetyl-Bis(N4-Methylthiosemicarbazone) (Cu-ATSM): Translational Studies for Internal Radiotherapy.},
 volume = {12},
 year = {2019}
}