权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
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
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/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

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）：