Radiation Protectors and Radiation Therapy Coupled Chemoprevention

放射防护器和放射治疗联合化学预防

• 批准号: 7846235
• 负责人: DAVID J. GRDINA
• 金额: $ 32.37万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846235
• 关键词: Acids; Acute Myelocytic Leukemia; Address; Adult; Adverse effects; Affect; Alkylating Agents; Alkylating Antineoplastic Agents; Amifostine; Animal Testing; Animals; Anticarcinogenic Agents; Base Pairing; Biological Assay; Biological Availability; Cancer Patient; Carmustine; Cells; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Chemotherapy-Oncologic Procedure; Childhood; Chronic; Cisplatin; Clinical; Combined Modality Therapy; Complex; Coupled; Couples Therapy; Cyclophosphamide; Cytoprotection; Cytoprotective Agent; DNA Damage; Descriptor; Development; Diagnosis; Disease; Dose; Drug usage; Dysmyelopoietic Syndromes; Effectiveness; Ethylnitrosourea; Evaluation; Exhibits; Experimental Neoplasms; Exposure to; FDA approved; Frameshift Mutation; General Population; Genomics; Goals; Grant; Guanine; Head and Neck Cancer; Health; Hematopoietic; Hematopoietic stem cells; Hour; Human; Hypoxanthines; Incidence; Individual; Induced Mutation; Investigation; Ionizing radiation; Kidney; Knock-in Mouse; Laboratories; Lateral; Lesion; Long-Term Survivors; Lung; Lung nodule; Lymphocyte; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Mediating; Metastasis Induction; Modality; Modeling; Molecular; Monitor; Mus; Mutagenesis; Mutation; Myeloid Leukemia; Names; Neoplasm Metastasis; Nodule; Non-Small-Cell Lung Carcinoma; Normal Cell; Oral; Package Insert; Parotid Gland; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phase; Pilot Projects; Population; Postoperative Period; Predictive Value; Predisposition; Primary Neoplasm; Process; Property; Protocols documentation; Radiation; Radiation therapy; Radiation-Protective Agents; Radio; Regimen; Relative (related person); Resources; Risk; Risk Factors; Schedule; Second Primary Cancers; System; Tail; Testing; Therapeutic; Therapeutic Agents; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome; Time; Toxic effect; Transferase; Treatment Efficacy; Treatment Protocols; Treatment-Related Cancer; Validation; Veins; Wild Type Mouse; Work; Xerostomia; analog; artificial lung; base; cancer cell; cancer prevention; cancer therapy; carcinogenesis; cell killing; chemotherapeutic agent; chemotherapy; cytotoxic; design; dosage; effective therapy; improved; irradiation; killings; leukemia; leukemogenesis; mouse model; neoplastic; neoplastic cell; novel; oncology; outcome forecast; phosphorothioate; prevent; promoter; public health relevance; radiation effect; research study; response; stem; success; treatment strategy; tumor; tumor growth

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. PUBLIC HEALTH RELEVANCE: This grant addresses the growing health problem of cancer patients cured of their first cancer by radiation and chemotherapy only to be diagnosed in later years with a cancer induced by those therapies. By appropriately administering to patients at the time of their radiation and chemotherapies cancer prevention drugs that can prevent mutations and cancer development without affecting the direct killing of cancer cells, patients will continued to be cured but without the risk of developing new cancers due to their treatments.

描述（由申请人提供）： 放疗和化疗的使用已经导致儿童和成人癌症患者的治愈率稳步提高。然而，这种治疗成功受到长期存活者中继发性癌症频繁发展的限制。治疗相关癌症的实例包括骨髓增生异常综合征和急性髓性白血病。这些肿瘤性疾病是治疗诱导的造血干细胞DNA损伤的结果。具有潜在可治愈癌症的患者代表了制定继发性恶性肿瘤化学预防策略的关键人群。该提案的目标是鉴定、表征和验证可以防止造血干细胞突变损伤同时保留放疗和化疗方案的抗肿瘤功效的药剂。这种新型的放射防护剂介导的化学预防被称为治疗偶联化学预防（TCC）。为了促进这些研究，我们将使用MLL-ELL基因敲入小鼠模型，该模型密切再现了在人类相关急性髓性白血病中观察到的多步转化过程。这些MLL-ELL基因敲入小鼠不会自发地发生白血病，但在暴露于DNA损伤剂后表现出对白血病的高度易感性。该模型将提供一种新的和独特的资源，以测试和验证TCC策略的患者在继发性癌症的风险。待检查的TCC试剂是氨磷汀和膦酰基，其各自在比证明经典细胞保护所需的剂量低4- 16倍的剂量下具有抗诱变特性。我们将确定这些TCC剂在用电离辐射和烷基化化疗剂如环磷酰胺治疗的具有4天大FSa“人工”微肺转移的小鼠中的最大非细胞保护剂量。使用Hprt突变试验，我们将评估TCC药物在MLL-ELL基因敲入小鼠及其野生型对应小鼠中暴露于电离辐射和烷化剂治疗后的抗突变有效性。使用MLL-ELL基因敲入小鼠模型，我们还将评估TCC在同一动物系统中预防放射和烷化剂诱导的Hprt基因突变以及治疗相关急性髓性白血病发展的功效。公共卫生相关性：这项补助金解决了癌症患者日益严重的健康问题，他们的第一个癌症是通过放射和化学疗法治愈的，但在以后的几年里却被诊断出患有这些疗法引起的癌症。通过在患者接受放疗和化疗时适当给予癌症预防药物，可以预防突变和癌症发展，而不影响癌细胞的直接杀伤，患者将继续被治愈，但不会因治疗而出现新癌症的风险。