NOVEL NUCLEOSIDES FOR IMAGING DURING CANCER THERAPY

用于癌症治疗期间成像的新型核苷

• 批准号: 2540695
• 负责人: KYOICHI A WATANABE
• 金额: $ 12.5万
• 依托单位: CODON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2540695
• 关键词: cell line; chemical synthesis; enzyme substrate; enzyme substrate complex; fluorouracil; genetic transduction; herpes simplex virus 1; image enhancement; imaging /visualization /scanning; purine nucleosides; thymidine kinase

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.

描述：通过基因疗法治疗癌症，其中外源性 将基因导入肿瘤细胞，越来越受到人们的关注。 由编码的酶对特定底物的代谢 转导的基因产生对肿瘤有毒的物质。 在最 常见的方法是，疱疹病毒胸苷激酶的基因具有 是通过逆转录病毒转导引入的。 尽管充满希望， 治疗方案的制定受到困难的限制 确定转导效率和 HSV1-TK 范围 表达。 了解表达水平、最佳表达时间 应用基材，以及处理可行的时间 对指导临床医生具有重要价值。 一个 对细胞和组织进行成像的非侵入性临床方法 大大提高治疗成功的可能性。 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， 在动物肿瘤模型中被证明是一种有前途的成像底物 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、更具活性的底物，表现出更大的选择性 且特异性将具有相当大的价值。 基于 初步数据申请人建议合成一系列木糖- 核苷类似物（图 1）显示出增强的活性： HSV1-TK 的底物。 这些化合物将被放射性碘标记并 测试了基于细胞系的增强选择性和特异性 化验。 有前途的候选人将接受影像学活动测试 动物肿瘤模型中的底物。 在第二阶段，申请人将根据 第一阶段开发的先导药物。申请人将扩大临床前研究 测试有前途的候选人以确定药理学问题 清除、保留、器官分配等。他们还将发展 产生 HSV-TK 变体的程序。 这些都将受到挑战 与新化合物一起寻找最活跃的变体组合 酶和新型底物。