5-aza-2'-deoxycytidine /valproic acid for leukemia /myel

5-氮杂-2-脱氧胞苷/丙戊酸治疗白血病/myel

• 批准号: 6836200
• 负责人: GUILLERMO GARCIA-MANERO
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-09 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836200
• 关键词: CpG islands; DNA methylation; acetylation; amidohydrolases; antineoplastics; bone marrow disorder; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; deoxycytidine; enzyme inhibitors; gene expression; histones; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplasm /cancer relapse /recurrence; patient oriented research; pharmacokinetics; preneoplastic state; valproate

DESCRIPTION (provided by applicant): Treatment options for adult patients with leukemia remain sub-optimal, and therefore new rationally designed therapies are needed. Two epigenetic alterations are currently the focus of intense investigation: DNA methylation of promoter CpG islands, and changes in the histone code associated with distinct levels of chromatin compaction and gene expression. These are of interest because: 1) they are observed at high frequency in patients with leukemia; 2) both have a role in gene expression and are intimately associated; and 3) can be modulated using hypomethylating agents and histone deacetylase inhibitors (HDACI) with preclinical and clinical activity. Results of a phase I study of low-dose 5-aza-2'-deoxycytidine (decitabine), a hypomethylating agent, performed at our institution, have shown that decitabine has significant activity at doses of 15 mg/m2 daily X 10 days. Valproic acid is an oral anti-convulsant agent with potent HDACI activity at physiological doses, also with an excellent safety profile. Based on this, we propose the hypothesis that the combination of decitabine and valproic acid will be well tolerated and will have significant antileukemia activity. To test this hypothesis, we propose the following aim: to conduct a phase I/II study of low-dose decitabine with escalating doses of valproic acid. The study will be monitored for toxicity, clinical response, and changes in histone acetylation, DNA methylation and gene expression. This study will have important implications, as it will provide fundamental knowledge regarding the clinical and molecular implications in vivo of the combination of a DNA hypomethylating agent and a HDACI. Decitabine will be generously provided by SuperGen (r). Valproic acid is an FDA approved anti-convulsant.

描述（由申请人提供）：成人白血病患者的治疗方案仍然不够理想，因此需要新的合理设计的治疗方法。两种表观遗传改变是目前研究的重点：启动子CpG岛的DNA甲基化，以及与不同水平的染色质压实和基因表达相关的组蛋白代码的变化。这些是有趣的，因为：1)它们在白血病患者中观察到高频率；2)两者都参与基因表达并密切相关；3)可以使用低甲基化剂和具有临床前和临床活性的组蛋白去乙酰化酶抑制剂（HDACI）进行调节。低剂量5-氮杂-2'-脱氧胞苷（地西他滨）是一种低甲基化剂，在我们机构进行的一期研究结果表明，地西他滨在15mg /m2每日X 10天的剂量下具有显著的活性。丙戊酸是一种口服抗惊厥剂，在生理剂量下具有有效的HDACI活性，也具有良好的安全性。基于此，我们提出地西他滨与丙戊酸联用耐受性良好且具有显著抗白血病活性的假设。为了验证这一假设，我们提出以下目标：进行低剂量地西他滨与逐渐增加的丙戊酸剂量的I/II期研究。该研究将监测毒性、临床反应、组蛋白乙酰化、DNA甲基化和基因表达的变化。这项研究将具有重要的意义，因为它将提供关于DNA低甲基化剂和HDACI组合在体内的临床和分子意义的基础知识。地西他滨将由SuperGen (r)慷慨提供。丙戊酸是FDA批准的抗惊厥药。