Journal Article Validation of 64Cu-ATSM damaging DNA via high-LET Auger electron emission

D. McMillan, Dayton  ,  Maeda, Junko  ,  Justin, Bell  ,  D. Genet, Matthew  ,  Phoonswadi, Garrett  ,  A. Mann, Kelly  ,  L. Kraft, Susan  ,  Kitamura, Hisashi  ,  Fujimori, Akira  ,  Yoshii, Yukie  ,  Furukawa, Takako  ,  Fujibayashi, Yasuhisa  ,  Kato, Takamitsu

56 ( 5 )  , pp.784 - 791 , 2015-08 , Oxford University Press
Radioactive copper (II) (diacetyl-bis N4-methylthiosemicarbazone) (Cu-ATSM) isotopes were originally developed for the imaging of hypoxia in tumors. Because the decay of a 64Cu atom is emitting not only positrons but also Auger electrons, this radionuclide has great potential as a theranostic agent. However, the success of 64Cu-ATSM internal radiation therapy would depend on the contribution of Auger electrons to tumor cell killing. Therefore, we designed a cell culture system to define the contributions to cell death from Auger electrons to support or refute our hypothesis that the majority of cell death from 64Cu-ATSM is a result of high-LET Auger electrons and not positrons or other low-LET radiation. Chinese hamster ovary (CHO) wild type and DNA repair–deficient xrs5 cells were exposed to 64Cu-ATSM during hypoxic conditions. Surviving fractions were compared with those surviving gamma-radiation, low-LET hadron radiation, and high-LET heavy ion exposure. The ratio of the D10 values (doses required to achieve 10% cell survival) between CHO wild type and xrs5 cells suggested that 64Cu-ATSM toxicity is similar to that of high-LET Carbon ion radiation (70 keV/μm). γH2AX foci assays confirmed DNA double-strand breaks and cluster damage by high-LET Auger electrons from 64Cu decay, and complex types of chromosomal aberrations typical of high-LET radiation were observed after 64Cu-ATSM exposure. The majority of cell death was caused by high-LET radiation. This work provides strong evidence that 64Cu-ATSM damages DNA via high-LET Auger electrons, supporting further study and consideration of 64Cu-ATSM as a cancer treatment modality for hypoxic tumors.

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