GUANINE NUCLEOSIDES--POTENTIAL NEW THERAPEUTIC USES

鸟嘌呤核苷——潜在的新治疗用途

• 批准号: 2103023
• 负责人: JUSTIN D COHEN
• 金额: $ 10.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103023
• 关键词: DNA repair; Hodgkin's disease; acute lymphocytic leukemia; adduct; alkylating agents; animal tissue; cell cycle; cytotoxicity; deoxyribonucleoside triphosphate; gel electrophoresis; guanine nucleoside; high performance liquid chromatography; human tissue; immunomodulators; lymphoma; melphalan; neoplasm /cancer pharmacology; purine nucleoside phosphorylase; tissue /cell culture

Inhibition of DNA synthesis by a deoxynucleoside or a deoxynucleoside analogue can kill cells ("direct toxicity") and can also enhance the toxicity of alkylating agents ("sensitization"). Not surprisingly, the extent of direct toxicity correlates closely with the degree of sensitization. This proposal addresses T cell neoplasms which are unusually sensitive to direct toxicity by deoxyguanosine and uniquely and exquisitely sensitive to its analogue 9-beta-D-arabinofuranosylguanine ("araG"). One objective of this proposal is to use this unique sensitivity to selectively sensitize T cell neoplasms compared to normal hematopoietic progenitor cells responsible for dose-limiting clinical toxicity. Such T cell selective sensitization has clear potential applications in clinical treatment as well as in ex vivo purging of neoplastic T cells from bone marrow. A second objective is to determine the mechanisms of sensitization with the long term intention of extrapolating these mechanistic concepts to closely analogous sensitization approaches. In preliminary studies araG and deoxyguanosine did potently enhance alkylator toxicity producing 5 to 8 fold dose modifying effects in human T cell neoplasms but not in B cells. In sharp contrast, guanosine was non- toxic and strongly protected against alkylator toxicity in human T cell lines - despite depleting dCTP and dTTP pools to the same extent as did equimolar deoxyguanosine. Guanosine's surprising effect and the very different effect of araG may relate to metabolism of araG almost exclusively via the deoxycytidine kinase ("dCK") pathway and to metabolism of guanosine via the purine nucleoside phophorylase ("PNP") pathway. Deoxyguanosine, metabolized via both pathways, might sensitize T cell neoplasms (high dCK:PNP ratio) while simultaneously protecting non-T cells (low dCK:PNP). Using measures of nucleoside metabolism, DNA injury and repair, and new techniques for specifically identifying which aspects of DNA synthesis are being impaired, this proposal will test l) whether deoxyguanosine, araG or guanosine preferentially sensitize or protect human T cell malignancies relative to non-T cells including normal marrow progenitor cells, 2) whether deoxyguanosine can sensitize or protect depending on its metabolism via the dCK or PNP pathways, 3) whether guanosine protects by increasing guanylate ribonucleotides which then block cell cycle progression permitting greater repair of alkylator- injured DNA before cells initiate replicative synthesis, and 4) whether deoxyguanosine and araG cause direct toxicity and sensitization not only by depleting dCTP and dTTP but also by high dGTP and araGTP inhibiting DNA polymerases alpha, delta or epsilon.

通过脱氧核苷或脱氧核苷抑制DNA合成 模拟可以杀死细胞（“直接毒性”），也可以增强 烷基化剂的毒性（“敏化”）。 毫不奇怪， 直接毒性的程度与程度紧密相关 致敏。该建议解决了T细胞肿瘤 对脱氧鸟苷的直接毒性异常敏感，唯一的 对其类似物9-beta-d-arabinofuranosylguanine非常敏感 （“ Arag”）。 该提议的一个目的是使用此独特 与正常人相比，对选择性敏化T细胞肿瘤的敏感性 负责剂量限制临床的造血祖细胞 毒性。这样的T细胞选择性敏化具有明显的潜力 在临床治疗中的应用以及在体外清除 来自骨髓的肿瘤T细胞。第二个目标是确定 长期意图的致敏机制 将这些机械概念推断为紧密相似 致敏方法。 在初步研究中 烷基毒性在人类中产生5至8倍剂量的修饰作用 T细胞肿瘤，但不在B细胞中。相比之下，鸟嘌呤是非 - 有毒并强烈保护人类T细胞中的烷基毒性 线 - 尽管DCTP和DTTP池耗尽的程度与以下情况相同 等摩尔脱氧藻氨酸。鸟嘌呤的令人惊讶的效果和 ARAG的不同作用几乎与Arag的代谢有关 专门通过脱氧胞苷激酶（“ DCK”）途径和代谢 通过嘌呤核苷哲学酶（“ PNP”）途径的鸟嘌呤。 通过两种途径代谢的脱氧鸟苷可能使T细胞敏感 肿瘤（高DCK：PNP比），同时保护非T细胞 （低DCK：PNP）。使用核苷代谢，DNA损伤和 维修和新技术，以专门识别 DNA合成受到损害，该建议将测试l） 脱氧鸟苷，Arag或鸟苷优先敏感或保护 相对于非T细胞（包括正常骨髓）的人类T细胞恶性肿瘤 祖细胞，2）脱氧鸟苷是否可以敏感或保护 取决于其通过DCK或PNP途径的代谢，3）是否是否 鸟苷通过增加鸟苷酸核糖核苷酸来保护，然后 阻止细胞周期进程，允许对烷基烷基的修复进行更大的修复 细胞启动重复合成之前受伤的DNA，4）是否是否 脱氧鸟苷和Arag不仅引起直接毒性和敏感性 通过耗尽DCTP和DTTP，但也可以通过高DGTP和ARAGTP抑制DNA 聚合酶alpha，delta或epsilon。