Validation of⁶⁴Cu-ATSM damaging DNA via high-LET Auger electron emission

Abstract

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.

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells

“…RBE values were demonstrated to increase as LET increases in wild-type cells, while this association between LET level and RBE value was not observed in V3 cells. It was confirmed that radiosensitivity is dose-dependent in NHEJ-deficient cells but not LET-dependent, as was previously demonstrated (17,19). Therefore, disruption of NHEJ repair may not be the optimum strategy for the enhancement of tumor control using high LET radiation.…”

“…For monoenergetic beam irradiation, 13 and 70 keV/µm C ions, and 200 keV/µm Fe ions, were used. Monoenergetic C ions with an LET of 70 keV/µm were obtained by Lucite attenuation (17). For OptiCell (Thermo Fisher Scientific, Inc.) irradiation, C ions were accelerated to 290 MeV/n initial energy and spread out with a ridge filter to produce an SOBP of width 6 cm (18).…”

64CuCl2 PET/CT in Prostate Cancer Relapse

“…The additional emission of Auger electrons associated with the electron capture decay canal (electron capture, 43.075%) might considerably contribute to the possible therapeutic effectiveness of this radionuclide. Auger electrons have low kinetic energies and short-range penetration but concomitantly high linear-energy transfer (33), like heavier particles (34,35). The present study might provide the basis for evaluating the radiation safety of 64 CuCl 2 and estimating the dose absorbed by organs at risk in the case of theranostic application.…”

Relative biological effectiveness in canine osteosarcoma cells irradiated with accelerated charged particles

“…Carbon ions were accelerated at 290 MeV/nucleon of initial energy and spread out with a ridge filter for 6 cm width of SOBP. The monolayer cell culture was irradiated at the center (50 keV/µm of average LET) within the SOBP at a distance of 119 mm from the entrance (27). Monoenergetic protons that were accelerated to 70 MeV using the NIRS-930 cyclotron have a LET value of 1.0 at the irradiated position.…”