Radioactive copper (II) (diacetyl-bis N4-methylthiosemicarbazone) (Cu-ATSM) isotopes were originally developed for the imaging of hypoxia in tumors. 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/m). H2AX 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. = 8). Cell culture Wild-type CHO cells (CHO10B2) and the non-homologous end-joining (NHEJ) repair-deficient xrs5 cells (deficient) were graciously supplied by Dr Joel Bedford (Colorado State University, Fort Collins, CO) . Cell cultures were maintained in Eagle’s Minimal Essential Medium Alpha (MEM-) (Gibco, Indianapolis, IN) augmented with 10% heat inactivated fetal bovine serum (FBS, Sigma, St Louis, MO), 1% Penicillin and buy Irsogladine Streptomycin anti-microbial and 0.1% Fungizone antimycotic (Gibco). Cells were maintained in 5% CO2 at 37C in a humidified incubator. Cell doubling time is 12.3 h for CHO wild type and 15.0 h for xrs5 cells. Exponential growth cells were used for 64Cu-ATSM uptake measurement and all cell buy Irsogladine survival experiments. buy Irsogladine G1 cell synchronization was carried out for and in a hypoxic tumor model. J Nucl Med 1999;40:177C83. [PubMed] 3. Yoshii Y, Furukawa T, Kiyono Y, et al. Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) accumulates in rich regions of CD133+ buy Irsogladine highly tumorigenic cells in mouse colon carcinoma. Nucl Med Biol 2010;37:395C404. [PubMed] 4. Zweit J. Radionuclides and carrier molecules for therapy. Phys Med Biol 1996;41:1905C14. [PubMed] 5. Johnson TE, Birky BK. Health Physics and Radiological Health. 4th edn. Lippincott Williams & Wilkins, 2011. 6. Chapman JD, Urtasun RC, Blakely EA, et al. Hypoxic cell sensitizers and heavy charged-particle radiations. Br J Cancer Suppl 1978;3:184C8. [PMC free article] [PubMed] 7. Raju MR, Amols HI, Bain E, et al. A heavy particle comparative study. Part III: OER and RBE. Br J Radiol 1978;51:712C9. [PubMed] 8. Bertrand G, Maalouf M, Rabbit polyclonal to IL4 Boivin A, et al. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev 2014;10:114C26. [PubMed] 9. Cui X, Oonishi K, Tsujii H, et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res 2011;71:3676C87. [PubMed] 10. Howell RW. Radiation spectra for Auger-electron emitting radionuclides: Report No. 2 of AAPM Nuclear Medicine Task Group No. buy Irsogladine 6. Med Phys 1992;19:1371C83. [PubMed] 11. Obata A, Kasamatsu S, Lewis JS, et al. Basic characterization of 64Cu-ATSM as a radiotherapy agent. Nucl Med Biol 2005;32:21C8. [PubMed] 12. Avila-Rodriguez MA, Nye JA, Nickles RJ. Simultaneous production of high specific activity 64Cu and 61Co with 11.4 MeV protons on enriched 64Ni nuclei. Appl Radiat Isot 2007;65:1115C20. [PubMed] 13. Gingras B, Somorjai R, Bayley C. The preparation of some thiosemicarbazones and their copper complexes. Can J Chem 1961;39:973C85. 14. Fujibayashi Y, Cutler CS, Anderson CJ, et al. Comparative studies of Cu-64-ATSM and C-11-Acetate in an acute myocardial infarction model: imaging of hypoxia in rats. Nucl Med Biol 1999;26:117C21. [PubMed] 15. Jalilian AR, Rostampour N, Rowshanfarzad P, et al. Preclinical studies of [61Cu]ATSM as a PET radiopharmaceutical for fibrosarcoma imaging. Acta Pharm 2009;59:45C55. [PubMed] 16. Jeggo P, Kemp L. X-ray-sensitive mutants of Chinese hamster ovary cell line isolation and cross-sensitivity to other DNA-damaging agents. Mutat Res 1983;112:313C27. [PubMed] 17. Miller DL, Roth MB. are protected from lethal hypoxia by an embryonic diapause. Curr Biol 2009;19:1233C7. [PMC free article] [PubMed] 18. Seko Y, Tobe K, Ueki K, et al. Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein kinase kinase, mitogen-activated protein kinases, and S6 kinase in cultured rat cardiac myocytes. Circ Res 1996;78:82C90. [PubMed] 19. Kanai T, Endo M, Minohara S, et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys 1999;44:201C10. [PubMed] 20. Fujisawa H, Genik PC, Kitamura.