Radiation Protectors and Radiation Therapy Coupled Chemoprevention

描述(由申请人提供)： 放射和化疗的使用使儿童和成人癌症患者的治愈率稳步提高。然而，长期存活者继发性癌症的频繁发展限制了这种治疗的成功。与治疗相关的癌症包括骨髓增生异常综合征和急性髓系白血病。这些肿瘤性疾病是治疗诱导的造血干细胞DNA损伤的结果。潜在可治愈癌症患者是制定继发性恶性肿瘤化学预防策略的关键人群。这项建议的目标是鉴定、鉴定和验证可以防止造血干细胞突变损害的药物，同时保持放化疗方案的抗肿瘤效果。这种辐射保护剂介导的化学预防的新范例被称为治疗耦合化学预防(TCC)。为了促进这些研究，我们将使用MLL-ELL敲入小鼠模型，该模型紧密地概括了在人类相关的急性髓系白血病中观察到的多步骤转化过程。这些MLL-ELL敲入小鼠不会自发发生白血病，但在暴露于DNA损伤剂后表现出对白血病的高度敏感性。该模型将为有继发性癌症风险的患者提供一种新的和独特的资源来测试和验证TCC策略。要检查的TCC试剂是氨磷汀和膦醇，每种药物的剂量都具有抗突变特性，比证明经典细胞保护所需的剂量低4-16倍。我们将确定这些TCC制剂在接受电离辐射和烷化化疗药物(如环磷酰胺)治疗4天大的FSA“人工”微小肺转移瘤的小鼠中的最大非细胞保护性剂量。利用HPRT突变试验，我们将评估TCC制剂在MLL-ELL敲入小鼠及其野生型小鼠暴露于电离辐射和烷化剂治疗后的抗突变效果。使用MLL-ELL敲入小鼠模型，我们还将评估TCC在防止辐射和烷化剂诱导的HPRT基因突变以及在同一动物系统中发生与治疗相关的急性髓系白血病方面的有效性。

DESCRIPTION (provided by applicant): The use of radiation and chemotherapy has resulted in steadily improving cure rates in both childhood and adult cancer patients. This therapeutic success, however, has been limited by the frequent development of secondary cancers in long term survivors. Examples of therapy-related cancers include myelodysplastic syndrome and acute myeloid leukemia. These neoplastic disorders are a consequence of the therapy induced- DNA damage in hematopoietic stem cells. Patients with potentially curable cancers represent a critical population for the development of strategies for chemoprevention of secondary malignancies. The goals of this proposal are the identification, characterization, and validation of agents that can prevent mutational damage in hematopoietic stem cells while preserving the anti-tumor efficacy of radiation and chemotherapy regimens. This novel paradigm of radioprotector-mediated chemoprevention is known as therapy coupled chemoprevention (TCC). To facilitate these studies, we will use the MLL-ELL knock-in mouse model that closely recapitulates the multistep process of transformation observed in human-related acute myeloid leukemia. These MLL-ELL knock-in mice do not develop leukemia spontaneously, but exhibit a high susceptibility to leukemia following exposure to a DNA damaging agent. This model will provide a novel and unique resource to test and validate TCC strategies for patients at risk for secondary cancers. TCC agents to be examined are amifostine and phosphonol, which each possess anti-mutagenic properties at doses 4- to 16- fold lower than those required to demonstrate classical cytoprotection. We will determine the maximum non- cytoprotective doses of these TCC agents in mice having 4 day old FSa "artificial" micro lung metastases treated with ionizing radiation and an alkylating-chemotherapeutic agent such as cyclophosphamide. Using the Hprt mutation assay, we will assess the anti-mutagenic effectiveness of TCC agents in MLL-ELL knock-in mice and their wild type counterparts following exposure to ionizing radiation and alkylating agent therapy. Using the MLL-ELL knock-in mouse model, we will also evaluate the efficacy of TCC to prevent radiation- and alkylating agent-induced mutations at the Hprt locus and the development of therapy-related acute myeloid leukemia in the same anima system.