Radiation Protectors and Radiation Therapy Coupled Chemoprevention

放射防护器和放射治疗联合化学预防

基本信息

批准号：
8245173
负责人：
DAVID J. GRDINA
金额：
$ 31.4万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/8245173
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 Gene 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 Nitrosourea Compounds 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

项目摘要

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）：放射线和化学疗法的使用导致儿童和成人癌症患者的治愈率稳步提高。然而，这种治疗成功受到了长期幸存者中二级癌的频繁发展的限制。与治疗相关的癌症的例子包括骨髓增生综合征和急性髓样白血病。这些肿瘤疾病是造血干细胞中诱导的DNA损伤的结果。潜在可治愈的癌症患者代表着关键的人群，用于制定继发性恶性肿瘤的化学预防策略。该提案的目标是对可以防止造血干细胞中突变损害的药物的鉴定，表征和验证，同时保留了放射线和化学疗法方案的抗肿瘤疗效。辐射保护剂介导的化学预防的这种新型范式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敲入小鼠模型，该模型紧密概括了在人类相关的急性髓样白血病中观察到的多步转化过程。这些MLL-ELL敲入小鼠不会自发发展白血病，但暴露于DNA损伤剂后对白血病表现出很高的敏感性。该模型将提供一种新颖而独特的资源，以测试和验证患有次要癌症风险的患者的TCC策略。要检查的TCC药物是氨基氨酸和磷诺，它们具有抗糊状特性，其剂量的剂量比证明经典细胞保护作用所需的剂量低4至16倍。我们将确定这些TCC药物的最大非细胞保护剂剂量在具有4天大的FSA“人造”微肺转移和用电离辐射和烷基化化学治疗剂（如环磷酰胺）处理的小鼠中。使用HPRT突变测定法，我们将在暴露于电离辐射和烷基化剂疗法后，评估TCC药物在MLL-ELL敲入小鼠及其野生型同伴中TCC药物的抗毒素有效性。使用MLL-ELL敲入小鼠模型，我们还将评估TCC在HPRT基因座的辐射和烷基化剂诱导的突变的功效，并在同一Anima系统中开发与治疗相关的急性髓样白血病的发展。公共卫生相关性：该赠款解决了通过放射和化学疗法治愈其第一次癌症的癌症患者的日益严重的健康问题，仅在后来的几年被诊断为这些疗法引起的癌症。通过在辐射和化学疗法预防药物时适当地给患者施用，这些药物可以防止突变和癌症发育而不会影响癌细胞的直接杀死，患者将继续治愈，但由于其治疗而没有开发新癌症的风险。