Abstract 32: Suppression of medical radiation DNA damage in cancer susceptible and normal humans using a new aminothiol radioprotector

Abstract

Abstract CT scan usage has greatly increased in the last two decades, with an estimated 85 million U.S. CT scans done in 2011. These exams are valuable and greatly enhance patient care. Certain CT scan and radiology procedures deliver ionizing radiation doses of 10-70 mSv. 30% of CT scan patients require three or more CT scans, some as many as nine. Recent studies reported significant correlations between CT radiation doses and subsequent tumors in children and adults. A 2012 report showed a radiation dose-dependent relationship between chest irradiation (mean dose = 14 mSv) in BRCA1/2-carrying women under age 30 and subsequent breast cancer incidence. There is a concern that recurrent diagnostic doses of radiation increase a patient's lifetime cancer risk, particularly in people with genetic cancer susceptibility syndromes, e.g., Li-Fraumeni, Bloom's, ataxia-telangiectasia mutated (ATM) and BRCA1/2 mutation carriers. These patients, who could benefit from early and recurring cancer screening that includes diagnostic radiation may now avoid diagnostic radiology because of the cancer-associated risks. A new family of aminothiol radioprotectors was discovered in our laboratory; PrC-210 is the prototype. Initial PrC-210 efficacy in suppressing ionizing radiation-induced DNA damage was assessed with ex vivo irradiation of cells. Studies to date have demonstrated: i) using primary mouse splenocytes, a) phosphorylation of ATM (p-ATM) increased in a radiation dose-dependent manner and 20 mM PrC-210 pretreatment of cells minutes before 10 Gy irradiation suppressed ATM activation to background with 10 mM PrC-210 equal in effect to KU55933, an ATM kinase inhibitor and positive control, and b) γ-H2AX activation by 10 Gy irradiation was suppressed to background by prior addition of 5-10 mM PrC-210, ii) using human HEK-293 cells, the activation of NF-κB achieved with 10 Gy irradiation can be suppressed to background by 5 mM PrC-210 pretreatment minutes before irradiation. These results support the notion that PrC-210 can completely inhibit ionizing radiation-induced DNA damage response in primary lymphocytes and human HEK-293 cells at PrC-210 concentrations achievable in rodent blood at a non-toxic systemic dose (i.e., <0.5 MTD dose). Separate studies showed that PrC-210 was free of the nausea/vomiting and hypotension toxicities that were accurately recreated using amifostine controls in accepted ferret and rat models. PrC-210, administered orally or by IP injection, also conferred 100% survival against an otherwise 100% lethal dose (8,750 mGy) of whole-body radiation to mice or rats. A single oral dose of PrC-210 prior to a diagnostic radiation procedure such as CT may suppress, possibly to background, DNA damage and associated risks, even in patients with cancer susceptibility syndromes, thus changing their screening and standard of care paradigm. Citation Format: William E. Fahl, Shelly Wuerzberger-Davis, Shigeki Miyamoto. Suppression of medical radiation DNA damage in cancer susceptible and normal humans using a new aminothiol radioprotector. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 32. doi:10.1158/1538-7445.CANSUSC14-32