THYMIDYLATE SYNTHASE INHIBITORS IN HEAD AND NECK CANCER

描述(摘自申请者摘要)：这项研究的目的是 开发以机制为基础的选择性治疗HNSCC。 假设：1)ZD1694的作用机理(S)应为 为基于机理的药物序列设计提供依据 最佳的治疗效果。2)较高的治疗指数和治愈率 可实现与ZD1694和CPT-11顺序使用而不是组合使用。 低分化咽鳞状细胞癌细胞株(FaDu)和 颈部分化良好的表皮样癌(A253)，将是 用来开展概述的研究。具体目标：1)核实 ZD1694的体外细胞毒作用机制及临床意义 ZD1694与青蒿素活性代谢物SN38的协同作用 CPT-11是体内治疗选择性的预测指标。2)评估 循环胸苷对ZD1694作用机制的影响3) 证实ZD1694在体外实现的协同作用 和SN38通过顺序组合平行，具有更高的治疗效果 指标和治愈率。拟议的研究预计将提供一个 为头颈部肿瘤的临床方案设计提供合理依据。

DESCRIPTION (from applicant's abstract): The goal of this research is to develop mechanism-based selective therapy for the treatment of HNSCC. Hypotheses: 1) Delineation of mechanism(s) of actions of ZD1694 should provide the basis for the design of mechanism-based drug sequence for optimal therapeutic benefit. 2) Higher therapeutic index and cure rate can be achieved with ZD1694 and CPT-11 used in sequence than in combination. Cell lines representing poorly differentiated SCC of the pharynx (FaDu) and a well-differentiated epidermoid carcinoma of the neck (A253), will be utilized to carry out the studies outlined. Specific Aims: 1) Verify that mechanisms associated with in vitro cytotoxicity to ZD1694 and the synergistic interaction between ZD1694 and SN38, an active metabolite of CPT-11, are predictive for in vivo therapeutic selectivity. 2) Evaluate the effect of circulating thymidine on the mechanism of action of ZD1694. 3) Establish that the synergistic interaction achieved in vitro between ZD1694 and SN38 are paralleled by sequential combinations with higher therapeutic index and cure rate. The proposed studies are expected to provide a rational basis for the design of clinical protocols in head and neck cancer.