New Aminothiol Prevention of X-Ray-Induced Mouse Mutagenesis and Tumorigenesis

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): CT scan usage has increased exponentially in the last two decades, with 70 million CT scans done in the U.S. in 2007 alone. Diagnostic imaging and procedures like angiography/stent placement provide substantial patient benefit and healthcare cost savings. CT scans, or multiple scans done in 30% of CT patients, deliver ionizing radiation (IR) doses in the range at which excess cancers have been demonstrated: i) for pediatric leukemia's and brain tumors, ii) BRCA breast tumors, iii) atomic bomb survivors, and iv) other medical radiation groups. Although individual risk is small, the size of the at-risk population is in the tens of millions, thus it is estimated that up to 2.9% of future cancers in th U.S. may be related to diagnostic radiology procedures. Additionally, individuals with genomic instability syndromes such as Li-Fraumeni, ataxia- telangiectasia and BRCA-associated breast and ovarian cancers, are radiation sensitive, and these cancer- predisposed patients must often avoid diagnostic radiology even though they could greatly benefit from its use. We have designed, synthesized and tested for radioprotective efficacy, a new family of 17 aminothiols. The most effective one, PrC-210, i) scavenges ROS and protects DNA, ii) reversibly inhibits diploid human fibroblast growth (G1/S) enabling DNA repair, iii) following a non-toxic (0.5 X maximum tolerated dose) oral or IP dose to mice or rats, confers 100% survival against an otherwise 100% lethal (9,000 mGy) dose of whole- body radiation, and iv) does not elicit a nausea/vomiting nor hypotensive response in accepted animal models. In this study, we will determine if PrC-210 can suppress IR-induced DNA damage in mice. The endpoints we will use to assay PrC-210 radioprotective efficacy include suppression of IR-induced: i) DNA double-strand breaks via g-H2AX foci formation, ii) mutation of the hypoxanthine-guanine phosphoribosyl transferase (hprt) gene, and iii) tumor growth in genetically unstable, radiation-sensitive, p53+/- mutant mice. If the results show strong PrC-210 efficacy in suppressing IR-induced genomic insult and tumorigenesis, it would make PrC-210 an attractive candidate for clinical development to eliminate the cancer risk associated with diagnostic radiology exams. This would greatly impact the use and scope of these exams, potentially making them available to cancer predisposed patients.