STUDIES OF CHILDHOOD SOLID TUMORS

该计划项目的长期目标是提高治愈率 儿童恶性实体肿瘤的发病率，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多学科的努力来实现， 由7个项目和一个核心组成。主要的推动力将是 开发旨在克服问题的新代理和策略 抗药性。项目1将解决5- 氟尿嘧啶-亚叶酸钙在异种移植瘤中的相互作用 未经治疗的骨肉瘤。项目2涉及核苷 在正常细胞和RMS细胞中的运输，以定义可能的差异 导致制定改进的治疗策略。 项目3将研究横纹肌肉母细胞的分化和药物 与5.1 H11单抗结合，两者均在体外 在活体内。如果结合是特异的，抗体将被偶联。 为了“瞄准”这个毒剂的运送而进行辩护。 项目4将研究VP-16，即抗微管的相互作用 复方和异环磷酰胺治疗RMS和Ewing 肉瘤在体外，随后在体内。项目5将尝试 阐明长春新碱交叉耐药的机制 和RMS中的双官能性烷基化剂马法兰 异种移植物。项目6检查DNA修复的潜在作用 在RMS中获得对烷化剂的抵抗力 和尤因肉瘤细胞。项目7A应用基因技术 对实体瘤细胞的分析，目的是提纯 临床分期系统。药代动力学研究(项目7B) 将是I期和II期临床试验不可或缺的一部分 实验模型中的临床前研究。此外，我们 计划在以前未接受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“第二阶段-第三阶段试点”研究应该允许 对药物活性的估计比常规方法所能获得的 意思是。这个程序的另一个新奇的方面是使用人类 用于评价新药活性的肿瘤移植瘤 通过考虑项目1-6或项目6中的数据来确定优先级 I期或II期校外试验。所获得的信息将 补充或取代来自经典第二阶段试验的数据 确定第二-第三阶段试点研究的药物评价优先事项； 因为前者通常是在经过大量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、方案 管理和异种移植模型)在 核心。这里概述的研究计划应该提供新的 关于遗传分期和发病机制的信息 肿瘤发生，并作为发育的范例 儿童实体肿瘤的治疗学。

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.