CLINICAL TRIAL: A PHASE I STUDY OF VORINOSTAT AND TEMOZOLOMIDE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这是一项辛二酰苯胺异羟肟酸（SAHA）联合替莫唑胺治疗儿童和青少年复发性或难治性中枢神经系统肿瘤的I期研究。SAHA是组蛋白去乙酰化酶（HDAC）的抑制剂，可导致细胞周期转换停滞在G1和G2 M期。SAHA通过在酶的活性位点插入异羟肟基、大部分脂肪链和部分苯基氨基而与HDAC结合。将SAHA插入活性位点防止天然底物的结合并阻断酶促脱乙酰化。替莫唑胺是一种口服咪唑四嗪前药，其经历自发水解为活性代谢物MTIC，MTIC在O 6-鸟嘌呤和其他位点甲基化DNA。 由于我们推测SAHA预处理可能通过松弛DNA和增加对甲基化剂的敏感性来增强替莫唑胺的活性，因此我们将首先递增SAHA的剂量，同时将替莫唑胺的剂量保持在150 mg/m2/天× 5。先前的研究表明，这种替莫唑胺剂量耐受性良好，具有抗肿瘤活性的潜力。 如果SAHA的最高剂量表现为可耐受，则替莫唑胺剂量将增加至标准单药剂量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.