STUDIES IN CHILDHOOD SOLID TUMORS

儿童实体瘤研究

• 批准号: 2087115
• 负责人: PETER J HOUGHTON
• 金额: $ 169.14万
• 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 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2087115
• 关键词: child (0-11); human subject; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; pediatric neoplasm /cancer; rhabdomyosarcoma

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 恶性实体瘤儿童的发病率，特别是 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个项目和一个核心组成。 主要目标是 开发新的代理人和战略，旨在克服问题 抗药性的证据。 项目1将讨论5- 氟尿嘧啶-甲酰四氢叶酸相互作用在异种移植物中的先前 未经治疗的骨肉瘤 项目2涉及核苷 正常和RMS细胞中的转运，以确定可能 导致改进治疗策略的发展。 项目3将研究横纹肌母细胞分化和药物治疗 使用5.1 H11单克隆抗体结合，均在体外 和体内。 如果结合是特异性的，则抗体将被缀合 长春新碱，以“靶向”该药剂的递送。 项目4将研究VP-16、抗微管 化合物和异环磷酰胺治疗RMS和尤文综合征 肉瘤在体外，随后在体内。 第5章尝试 阐明长春新碱与非长春新碱交叉耐药的机制 以及RMS中的双功能烷化剂美法仑 异种移植 项目6研究DNA修复的潜在作用 在RMS获得对烷基化剂的抗性中， 和尤文肉瘤细胞。 项目7A应用遗传技术 分析实体肿瘤细胞， 临床分期系统 药代动力学研究（项目7 B） 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。 我们还 计划在以前未经治疗的患者中测试替代药物 晚期横纹肌肉瘤、骨肉瘤和尤文肉瘤（项目 7D）。 这些“第二-第三阶段试点”研究应该允许更真实的 药物活性的估计比传统的 手段 该计划的另一个新颖之处是使用人类 肿瘤异种移植物，以评价新药物的活性 通过考虑项目1-6或 校外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级， 由于前者通常在经过大量预处理的环境中进行， 对多种药物耐药的患者。 集中供养 (e.g.,生物统计咨询和数据管理，程序 给药和异种移植模型）在本文中提供。 核心 这里概述的研究计划应该提供新的 关于遗传分期和机制的信息 肿瘤发生，并作为一个发展的范例， 儿科实体瘤的治疗。