Multiple Administrations of 64Cu-ATSM as a Novel Therapeutic Option for Glioblastoma: a Translational Study Using Mice with Xenografts

Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using current
treatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia are
associated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progression
and recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1α
in tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapy
agent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatment
for glioblastoma. This compound can target the overreduced state under hypoxic conditions within tumors.
Clinical positron emission tomography studies using radiolabeled Cu-ATSM have shown that Cu-ATSM
accumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. To
evaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in mice
bearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) and
multiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dose
groups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverse
events. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting the
dose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of
64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential for
treating this fatal disease.

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Translational Oncology

巻 11, 号 1, p. 24-30, 発行日 2017-11

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2023-05-15 23:26:49.233151

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