CORE--CHEMOTHERAPY AND TOXICOLOGY

这一核心组件由实验室设施、设备和 将由拟议计划的三个项目共享的服务。 核心是概念上的面向服务。其目标将是提供 以及时、高效和具有成本效益的方式评价 可能处于不同阶段的候选药物的抗肿瘤活性 在拟议计划中的发展。评估的范围可能从初始 筛选(与相关标准试剂的细胞毒性比较)以详细 支持IND应用的评估(例如，剂量和治疗 调度优化)。评估将在一系列的 体外和体内模型配置为提供一种标准化的方法 活性未知但足够灵活的试剂的开发 为已知更多信息的代理提供定制方法。数据 从培养中的一组人类肿瘤细胞系中提取的蛋白质将提供额外的 选择体内模型(人肿瘤异种移植)的指南 药物活性的详细评估。这些研究可能会得到以下补充 在常规小鼠肿瘤模型中的评价。这种方法，尽管 非排他性，强调发现积极对抗的代理人的发展 实体瘤。数据将以比较IC50值的形式提供 来自体外研究和临床相关的终点(例如，治愈， 或延长治疗失败的时间)来自活体研究。 将在所有研究中评估剂量-反应关系。有限 还将进行初步毒理学评估。使用这些工具 药物开发决策中的数据将是以下各方合作的成果 核心组件负责人、核心联合负责人、单个项目 领导者，以及PI计划。

This core component is comprised of laboratory facilities, equipment, and services that will be shared by the three projects of the proposed program. The core is service-oriented in concept. Its objective will be to provide in a timely, efficient, and cost-effective manner the evaluation of the antitumor activity of candidate drugs that may be at various stages of development in proposed program. Evaluations may range from initial screening (cytotoxicity compared to relevant standard agents) to detailed evaluations in support of an IND application (e.g., dose and treatment schedule optimization). Evaluations will be conducted in an array of in vitro and in vivo models configured to provide a standardized approach to the development of agents with unknown activity but flexible enough to provide customized approaches for agents about which more is known. Data from a panel of human tumor cell lines in culture will provide additional guidance in the selection of in vivo models (human tumor xenografts) for detailed evaluation of drug activity. These studies may be complemented by evaluations in conventional murine tumor models. This approach, although not exclusive, emphasizes discovery an development of agents active against solid tumors. Data will be presented in terms of comparative IC50 values from in vitro studies and clinically relevant endpoints (e.g., cures, regressions, or prolonged time to treatment failure) from in vivo studies. Dose-response relationships will be assessed in all studies. Limited preliminary toxicological evaluations will also be conducted. Use of these data in drug development decision making will be a cooperative effort among the core component leader, the core co-leaders, the individual project leaders, and the program PI.