CLINICAL TRIAL: A PHASE I STUDY OF VORINOSTAT AND TEMOZOLOMIDE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这是一项针对复发或难治性中枢神经系统肿瘤的儿童和青少年患者的I期研究，采用琥珀酰亚胺和替莫唑胺联合应用。SAHA是一种组蛋白脱乙酰酶(HDAC)抑制剂，可导致细胞周期停滞于G1和G2M期。SAHA通过在酶的活性部位插入羟肟基、大部分脂肪链和部分苯氨基与HDAC结合。将SAHA插入活性部位可阻止与天然底物的结合，并阻止酶去乙酰化。替莫唑胺是一种口服咪唑四氮类前药，可自发水解为活性代谢物MTIC，MTIC在O6-鸟嘌呤和其他位置上使DNA甲基化。 由于我们推测SAHA的预治疗可能通过松弛DNA和增加对甲基化药物的敏感性来增强替莫唑胺的活性，我们将首先增加SAHA的剂量，同时将替莫唑胺的剂量保持在150 mg/m2/天×5。以前的研究表明，这个剂量的替莫唑胺耐受性很好，具有潜在的抗肿瘤活性。如果SAHA的最大剂量似乎可以耐受，那么替莫唑胺的剂量将增加到标准的单药剂量200 mg/m2/天。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a phase I study of suberoylanilide hydroxamic acid (SAHA) plus temozolomide for children and adolescents with recurrent or refractory central nervous system tumors. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. SAHA binds to HDAC by inserting a hydroxamic group, most of the aliphatic chain and part of the phenyl amino group in the active site of the enzyme. The insertion of SAHA into the active site prevents the binding of the natural substrate and blocks enzymatic deacetylation. Temozolomide is an oral imidazotetrazine prodrug that undergoes spontaneous hydrolysis to the active metabolite MTIC, which methylates DNA at O6-guanine and other sites. Since we theorize that pretreatment with SAHA may potentiate the activity of temozolomide by relaxing DNA and increasing susceptibility to methylating agents, we will first escalate the dose of SAHA while holding the temozolomide dose constant at 150 mg/m2/day x 5. Previous studies suggest this temozolomide dose is well tolerated and has potential for antitumor activity. If the highest dose of SAHA appears tolerable, then temozolomide dosing will be increased to the standard single-agent dose of 200 mg/m2/day.