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

描述（由申请人提供）：CT扫描的使用在过去二十年中呈指数增长，仅2007年美国就完成了7000万次CT扫描。诊断成像和诸如血管造影/支架置入术之类的程序为患者提供了大量的好处，并节省了医疗成本。CT扫描，或在30%的CT患者中进行多次扫描，提供的电离辐射（IR）剂量在已经证明过量癌症的范围内：i)儿童白血病和脑肿瘤，ii) BRCA乳腺肿瘤，iii)原子弹幸存者，iv)其他医疗辐射组。尽管个体风险很小，但风险人群的规模高达数千万，因此据估计，在美国，高达2.9%的未来癌症可能与诊断放射学程序有关。此外，具有基因组不稳定综合征的个体，如Li-Fraumeni，共济失调-毛细血管扩张和brca相关的乳腺癌和卵巢癌，对辐射敏感，这些癌症易感患者必须经常避免诊断放射学，即使他们可以从使用放射学中受益匪浅。我们设计、合成并测试了一个新的17个氨基硫醇家族的辐射防护功效。最有效的一种，PrC-210, i)清除活性氧并保护DNA， ii)可逆地抑制二倍体人成纤维细胞生长（G1/S），使DNA修复，iii)小鼠或大鼠在无毒（最大耐受剂量的0.5倍）口服或IP剂量后，在100%致死（9,000 mGy）全身辐射剂量下获得100%的存活率，iv)在公认的动物模型中不会引起恶心/呕吐或低血压反应。在这项研究中，我们将确定PrC-210是否可以抑制ir诱导的小鼠DNA损伤。我们将用于检测PrC-210辐射防护效果的终点包括抑制ir诱导的：i)通过g-H2AX灶形成的DNA双链断裂，ii)次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（hprt）基因突变，以及iii)遗传不稳定、辐射敏感、p53+/-突变小鼠的肿瘤生长。如果结果显示PrC-210在抑制ir诱导的基因组损伤和肿瘤发生方面有很强的功效，那么PrC-210将成为临床开发的有吸引力的候选者，以消除与诊断放射检查相关的癌症风险。这将极大地影响这些检查的使用和范围，可能使易患癌症的患者也能使用这些检查。

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.