THYMIDYLATE SYNTHASE INHIBITORS IN HEAD AND NECK CANCER

描述（来自申请人摘要）：本研究的目标是 开发基于机制的选择性治疗HNSCC。 假设：1）ZD 1694作用机制的描述应 为基于机理的药物序列设计提供依据， 最佳治疗效益。 2)较高的治疗指数和治愈率， ZD 1694和CPT-11顺序使用比联合使用更容易实现。 代表咽部低分化SCC的细胞系（FaDu）和 颈部高分化表皮样癌（A253），将 用于进行概述的研究。 具体目标：1）验证 与ZD 1694的体外细胞毒性相关的机制， ZD 1694和SN 38（一种活性代谢物）之间的协同相互作用 CPT-11预测体内治疗选择性。 2)评价 循环胸苷对ZD 1694作用机制的影响。 第三章 确定ZD 1694和ZD 1694之间的体外协同相互作用 SN 38和SN 38通过具有较高治疗性的顺序组合而被抑制。 指标和治愈率。 预计拟议的研究将提供一个 为头颈部肿瘤临床治疗方案的设计提供了合理的依据。

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.