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 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-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 64Cu-ATSM.