Presentation 64Cu-ATSM internal radiotherapy targeting tumor malignant regions: sensitization based on its biological characteristics

Yoshii, Yukie  ,  Furukawa, Takako  ,  Matsumoto, Hiroki  ,  Yoshimoto, Mitsuyoshi  ,  Ming-Rong, Zhang  ,  Kiyono, Yasushi  ,  Fujibayashi, Yasuhisa  ,  Saga, Tsuneo

64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) is a promising theranostic agent targeting over-reduced condition under hypoxia in tumors. Clinical studies on diagnosis with radiolabeled Cu-ATSM are currently conducted worldwide, revealing its prognostic value. However, detailed characteristics of the region of high 64Cu-ATSM uptake remained unclear. Here, using human colon carcinoma HT-29 model, we investigated characteristics of 64Cu-ATSM uptake regions relating to tumor malignancy, such as up-regulation of DNA repair and concentration of CD133+ cancer stem cells, and developed a strategy to enhance 64Cu-ATSM internal radiotherapy efficacy by inhibiting DNA repair with co-administration of nucleic acid (NA) antagonists. Methods: Distribution of 64Cu-ATSM was examined in HT29 tumors, and the samples from regions identified as 64Cu-ATSM high- and low-uptake regions were used for characterization. Gene expression profile, NA incorporation (BrdU uptake), and CD133+ cell ratio were studied. For in vivo treatment study, 64Cu-ATSM (37 MBq) injection with or without co-administration of NA antagonists was tested and compared to 64Cu-ATSM alone (37 or 74 MBq). Results: Up-regulation of the pathways related to DNA repair along with BrdU uptake, and elevated CD133+ cell ratio were observed in 64Cu-ATSM high-uptake regions. In treatment study, 64Cu-ATSM showed dose-dependent inhibition of tumor growth, although 74 MBq showed significant toxicity. Co-administration of NA antagonists with 37 MBq 64Cu-ATSM showed greater tumor growth suppression than 74 MBq 64Cu-ATSM alone, without significant toxicity, and effectively reduced CD133+ cell ratio. Conclusions: 64Cu-ATSM accumulation was associated with tumor malignant characteristics and 64Cu-ATSM therapy with NA antagonists could be an effective approach to target these characteristics.
The Society of Nuclear Medicine (SNM) annual meeting 2015

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