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

Yoshii, Yukie  ,  Hiroki Matsumoto  ,  Yoshimoto, Mitsuyoshi  ,  Ming-Rong, Zhang  ,  Ooe, Yoko  ,  Kurihara, Hiroaki  ,  Narita, Yoshitaka  ,  Zhao-Hui, Jin  ,  Tsuji, Atsushi  ,  Yoshinaga, Keiichiro  ,  Fujibayashi, Yasuhisa  ,  Higashi, Tatsuya

11 ( 1 )  , pp.24 - 30 , 2017-11 , ELSEVIER
Glioblastoma is the most aggressive malignant brain tumor in humans and is difficult to cure using currenttreatment options. Hypoxic regions are frequently found in glioblastoma, and increased levels of hypoxia areassociated with poor clinical outcomes of glioblastoma patients. Hypoxia plays important roles in the progressionand recurrence of glioblastoma because of drug delivery deficiencies and induction of hypoxia-inducible factor-1αin tumor cells, which lead to poor prognosis. We focused on a promising hypoxia-targeted internal radiotherapyagent, 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), to address the need for additional treatmentfor 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-ATSMaccumulates in glioblastoma and its uptake is associated with high hypoxia-inducible factor-1α expression. Toevaluate the therapeutic potential of this agent for glioblastoma, we examined the efficacy of 64Cu-ATSM in micebearing U87MG glioblastoma tumors. Administration of single dosage (18.5, 37, 74, 111, and 148 MBq) andmultiple dosages (37 MBq × 4) of 64Cu-ATSM was investigated. Single administration of 64Cu-ATSM in high-dosegroups dose-dependently inhibited tumor growth and prolonged survival, with slight and reverse signs of adverseevents. Multiple dosages of 64Cu-ATSM remarkably inhibited tumor growth and prolonged survival. By splitting thedose of 64Cu-ATSM, no adverse effects were observed. Our findings indicate that multiple administrations of64Cu-ATSM have effective antitumor effects in glioblastoma without side effects, indicating its potential fortreating this fatal disease.

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