STUDIES OF CHILDHOOD SOLID TUMORS

儿童实体瘤的研究

• 批准号: 3093034
• 负责人: WILLIAM M CRIST
• 金额: $ 137.66万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-08-01 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3093034
• 关键词: biomedical facility; child (0-11); neoplasm /cancer chemotherapy; pediatric neoplasm /cancer

The long-term goal of this program project is to improve cure rates among children with malignant solid tumors, especially rhabdomyosarcoma (RMS), Ewing sarcoma and osteosarcoma. This aim will be pursued by a coordinated multidisciplinary effort, consisting of 7 projects and a CORE. The major thrust will be to develop new agents and strategies designed to overcome problems of drug resistance. Project 1 will address the efficacy of 5- fluorouracil-leucovorin interactions in xenografts of previously untreated osteosarcoma. Project 2 deals with nucleoside transport in normal and RMS cells to define differences that could lead to the development of improved treatment strategies. Project 3 will investigate rhabdomyoblast differentiation and drug binding with use of the 5.1 H11 monoclonal antibody, both in vitro and in vivo. If binding is specific, the antibody will be conjugated to vincristine in an effort to "target" the delivery of this agent. Project 4 will examine the interaction of VP-16, antimicrotubule compounds and ifosfamide in treatment of RMS and Ewing sarcoma in vitro, and subsequently in vivo. Project 5 will attempt to clarify the mechanisms of cross resistance between vincristine and the bifunctional alkylating agent melphalan in RMS xenografts. Project 6 examines the potential role of DNA repair in the acquisition of resistance to the alkylating agents by RMS and Ewing sarcoma cells. Project 7A applies genetic techniques to the analysis of solid tumor cells with the aim of refining clinical staging systems. Pharmacokinetic studies (Project 7B) will be an integral part of phase I and II clinical trials and preclinical investigations in experimental models. Further, we plan to test alternative agents in previously untreated patients with advanced RMS, osteosarcoma and Ewing sarcoma (Project 7D). These "phase II-III pilot" studies should permit truer estimates of drug activity than can be gained by conventional means. Another novel aspect of this program is the use of human tumor xenografts to evaluate the activity of new agents prioritized by considering data from Project 1-6 or from extramural phase I or II trials. The information gained will supplement or supercede data from classic phase II trials in determining drug evaluation priorities for phase II-III pilot studies, since the former are often performed in heavily pretreated patients with resistance to multiple agents. Centralized support (e.g., biostatistical consultation and data management, program administration, and xenograft models) are provided within the CORE. The research program outlined here should provide new information regarding genetic staging and mechanisms of oncogenesis, and serve as a paradigm for developmental therapeutics in pediatric solid tumors.

该计划项目的长期目标是提高治愈率 儿童恶性实体瘤的发病率，尤其是 横纹肌肉瘤（RMS）、尤文肉瘤和骨肉瘤。 这一目标将通过协调的多学科努力来实现， 由 7 个项目和一个 CORE 组成。 主要推动力将是 开发新的药物和策略来克服问题 的耐药性。 项目 1 将解决 5- 以前的异种移植物中氟尿嘧啶-亚叶酸相互作用 未经治疗的骨肉瘤。 项目2涉及核苷 正常细胞和 RMS 细胞中的转运来定义可能的差异 导致改进治疗策略的发展。 项目3将研究横纹肌细胞分化和药物 5.1 使用 H11 单克隆抗体进行结合，均为体外 和体内。 如果结合是特异性的，抗体将被缀合 长春新碱以努力“靶向”该药物的递送。 项目 4 将检查 VP-16、抗微管的相互作用 化合物和异环磷酰胺治疗 RMS 和 Ewing 肉瘤在体外，随后在体内。 项目5将尝试 阐明长春新碱之间的交叉耐药机制 以及 RMS 中的双功能烷化剂美法仑 异种移植物。 项目 6 研究 DNA 修复的潜在作用 通过 RMS 获得对烷化剂的抗性 和尤文肉瘤细胞。 项目7A应用遗传技术 分析实体瘤细胞以精炼 临床分期系统。 药代动力学研究（项目7B） 将成为 I 期和 II 期临床试验的组成部分 实验模型的临床前研究。 此外，我们 计划在以前未经治疗的患者中测试替代药物 患有晚期 RMS、骨肉瘤和尤文肉瘤（项目 7D）。 这些“II-III 期试点”研究应该允许更真实的 与传统方法相比，药物活性的估计 方法。 该程序的另一个新颖之处是使用人类 肿瘤异种移植物以评估新药的活性 通过考虑来自项目 1-6 或来自项目 1-6 的数据来确定优先级 外部 I 期或 II 期试验。 获得的信息将 补充或取代经典 II 期试验的数据 确定 II-III 期试点研究的药物评价优先事项， 因为前者通常是在经过严格预处理的情况下进行的 对多种药物耐药的患者。 集中支持 （例如，生物统计咨询和数据管理、计划 管理和异种移植模型）在 核。 这里概述的研究计划应该提供新的 有关遗传分期和机制的信息 肿瘤发生，并作为发育的范例 儿科实体瘤的治疗。