Abstract 4909: Novel radiation mitigators and cancer chemoprevention drugs

Abstract

The possibility of a radiation disaster from a nuclear detonation or accident has existed for over 50 years and spawned much of the basic research in radiobiology in the 1950-60s. The recent Fukushima accident was yet another reminder that there remains a dire need to develop novel therapies against radiation-induced toxicities. Here we report on the development of two novel radiation countermeasure therapies: Yel001 and Yel002. These small, biologically active, drug-like molecules were uncovered in the DEL high throughput assay reducing radiation-induced cyto- and geno-toxicity in yeast. Radiation-modulating activity was further confirmed in yeast plate-based DEL Assay: addition of either Yel001 or Yel002 to irradiated cultures reduced cell death and genomic instability. Further, Yel compounds increases survival to 75% in vivo following an LD100/30 dose of ionizing radiation (IR) with the first therapeutic injection administered 24 hours post exposure followed by injections at 48,72,96, and 120 hours. Additionally, treatment with Yel001 and Yel002 compounds reduces radiation-induced leukemia from 90% to to 50% and 40% respectively. Of note, treatment with either Yel001 or Yel002 reduced spontaneous leukemia rate from 10% to 0%. Furthermore, Yel002 significantly prolonged the life of Atm deficient mice. Treatment with Yel002 following IR accelerates the recovery of the hematopoietic cells and protects stem cells after sub-lethal exposures. In addition, treatment with Yel002 reduces I131, EMS, MMS, UV, cigarette smoke extract as well as nitrogen mustard induced toxicity as well as genotoxicity showing a broad application spectrum. Proteomics shows that Yel002 induces DNA repair mediated by Atm signaling, homologous recombination, nonhomologous end joining, base excision repair, DNA damage binding proteins and chromosome segregation functions. Toxicity has not been observed in neither in vitro or in vivo administrations, even in a two generation teratogenicity assay. Overall, Yel compounds have much potential as stockpile therapies for radiation-induced lethality and cancer as well as spontaneous cancer: they are highly effective when administered up to 24hours post exposure, they reduce radiation-induced sequelae such as leukemia, and appear to have an acceptable toxicity profile. Citation Format: Robert H. Schiestl, Yelena Rivina, Michael Davoren. Novel radiation mitigators and cancer chemoprevention drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4909. doi:10.1158/1538-7445.AM2014-4909