NOVEL NUCLEOSIDES FOR IMAGING DURING CANCER THERAPY

描述：通过基因疗法治疗癌症，其中外源性 基因被导入肿瘤细胞，正受到越来越多的关注。 编码的酶对特定底物的代谢 转导的基因会产生一种对肿瘤有毒的物质。在大多数情况下 常见的方法是，疱疹病毒胸苷激酶基因有 是通过逆转录病毒转导引入的。尽管前景看好， 治疗方案的发展受到以下困难的限制 HSV1-TK转导效率和程度的测定 表情。关于表达水平的知识，最佳时间 应用底物，以及处理可行的时间 对指导临床医生有相当大的价值。一个 对细胞和组织进行成像的非侵入性临床方法 极大地提高了治疗成功的可能性。 在申请人的早期工作中，放射性碘化氟尿嘧啶类似物FIAU， 在动物肿瘤模型中被证明是一种有希望的成像基质 具有可接受的选择性和专一性。尽管这些数据是 鼓舞人心的、更活跃的底物，表现出更高的选择性 而特异性将具有相当大的价值。基于 初步数据申请者建议合成一系列木糖- 显示增强活性的核苷类似物(图1) HSV1-TK的底物。这些化合物将被放射性碘标记并 在细胞系中测试增强的选择性和特异性 化验。有希望的候选人将接受成像活动测试 动物肿瘤模型中的底物。 在第二阶段，申请者将开发更多的基于 在第一阶段开发的线索申请者将扩大临床前 对有希望的候选人进行测试，以确定 清除、保留、器官分配等。它们还将发展 生产HSV-TK变种的程序。这些都将受到挑战 用新化合物寻找最活跃的变异体组合 酶和新型底物。

DESCRIPTION: Cancer treatment by gene therapy, in which an exogenous gene is introduced into tumor cells, is receiving increasing attention. Metabolism of a specific substrate by the enzyme encoded by the transduced gene produces a substance toxic to the tumor. In the most common approach, the gene for the Herpes Virus Thymidine Kinase has been introduced by retroviral transduction. Although promising, development of treatment protocols is limited by the difficulty of determining the efficiency of transduction and the extent of HSV1-TK expression. Knowledge of the level of expression, the optimal time for application substrate, and the time over which treatment is feasible would be of considerable value in guiding the clinician. A noninvasive, clinical method for imaging cells and tissues would greatly enhance the likelihood of successful therapy. In applicants earlier work a radioiodinated fluorouracil analogue, FIAU, was shown in an animal tumor model to be a promising imaging substrate with acceptable selectivity and specificity. Although these data were encouraging, more active substrates which display greater selectivity and specificity would be of considerable value. Based on the preliminary data applicants propose to synthesize a series of xylo- nucleoside analogues (Figure 1) that show enhanced activity as substrates for HSV1-TK. These compounds will be radioiodinated and tested for enhanced selectivity and specificity in a cell line based assay. Promising candidates will be tested for activity as imaging substrates in an animal tumor model. In Phase II applicants will develop additional compounds based on the leads developed in Phase I. The applicants will expand the preclinical testing of promising candidates so as to define pharmacologic issues of clearance, retention, organ distribution, etc. They will also develop a program to produce variants of the HSV-TK. These will be challenged with the new compounds to find the most active combination of variant enzyme and novel substrate.