NOVEL NUCLEOSIDES FOR IMAGING DURING CANCER THERAPY

描述：通过基因疗法治疗癌症，其中外源性 基因导入肿瘤细胞，正受到越来越多的关注。 代谢特定底物的酶编码的代谢 转导的基因产生对肿瘤有毒的物质。 最 常见的方法，疱疹病毒胸苷激酶的基因， 通过逆转录病毒转导引入。 虽然前景看好， 治疗方案的发展受到以下困难的限制： 确定转导效率和HSV 1-TK的程度 表情 知识的表达水平，最佳的时间， 施用基质，以及处理可行的时间 将在指导临床医生方面具有相当大的价值。 一 用于成像细胞和组织的非侵入性临床方法将 大大提高了治疗成功的可能性。 在申请人早期的工作中，放射性碘标记的氟尿嘧啶类似物FIAU， 在动物肿瘤模型中显示是一种有前途的成像基质 具有可接受的选择性和特异性。 虽然这些数据是 令人鼓舞的是，活性更高的底物显示出更大的选择性 和特异性将具有相当大的价值。 基于 初步数据申请人提出合成一系列木糖， 核苷类似物（图1）显示出增强的活性， HSV 1-TK的底物。 这些化合物将被放射性碘标记， 测试了基于细胞系的增强的选择性和特异性 比色法 有希望的候选人将被测试的活动作为成像 在动物肿瘤模型中， 在第二阶段，申请人将开发其他化合物， 在第一阶段开发的电极导线。 申请人将扩大临床前 测试有希望的候选物，以确定药理学问题， 清除，保留，器官分布等。它们还将发展 产生HSV-TK变体的程序。 这些都将受到挑战 与新的化合物，以找到最有效的组合， 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.