ZOSUQUIDAR TRIHYDROCHLORIDE DURING CONVENTIONAL INDUCTION AND POST-REMISSION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。接受新诊断的急性髓系白血病(AML)治疗的老年人(定义为年龄大于55岁至60岁)的缓解率和中位总存活率分别约为50%和12个月。化疗耐药是导致预后不良的主要原因。多药耐药蛋白(MDR1)介导的药物主动外排是化疗耐药的一个非常典型的机制。MDR1的表达与缓解率降低和中位总生存期相关。因此，抑制mdr1介导的外排可能会改善治疗结果。盐酸佐舒奎达(LY335979)是一种特异而有效的MDR1介导的外排调节剂。此外，它与柔红霉素的药代动力学相互作用最小，柔红霉素是治疗AML的基本药物。目前的临床试验需要收集和保存血浆样本，以便在安慰剂或佐舒奎达存在的情况下进行柔红霉素和阿糖胞苷的药代动力学分析。处理全血样本需要得到GCRC的支持。患者不会在GCRC上接受礼仪治疗。新诊断的AML或晚期MDS患者将被送往5N大学医院的保护环境室。患者将在安慰剂或佐舒奎达的基础上接受常规的诱导化疗(每天给予三剂柔红霉素并持续滴注阿糖胞苷)，每天六小时，每剂柔红霉素。患者将在服用第三剂柔红霉素之前和接下来的四天内采集血液样本，用于柔红霉素和阿糖胞苷的药代动力学分析(6个样本)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The remission rate and median overall survival of older adults (defined as age greater than 55 to 60 years of age) who are treated for newly diagnosed acute myeloid leukemia (AML) is approximately 50% and 12 months respectively. The primary reason for the poor prognosis is chemotherapy resistance. A very well characterized mechanism of chemotherapy resistance is the active efflux of drug medicated by the multdrug resistance protein (MDR1). The expression of MDR1 correlates with a reduced remission rate and median overall survival. Therefore, inhibition of MDR1 mediated efflux may improve treatment outcome. Zosuquidar trihydrochloride (LY335979) is a specific and potent modulator of MDR1-mediated efflux. Furthermore, it has minimal pharmacokinetic interactions with daunorubicin, an essential drug in the treatment of AML. The current clinical trial requires the collection and preservation of plasma samples for pharmacokinetic analysis of daunorubicin and cytarabine in the presence of placebo or Zosuquidar. The support of the GCRC is requested to process the samples of whole blood. Patients will not receive protocol therapy on the GCRC. Patients with newly diagnosed AML or advanced MDS will be admitted to the protected environment rooms of 5N University Hospital. Patients will receive conventional induction chemotherapy (three doses of daunorubicin given daily and continuous infusion of cytarabine) in addition to either placebo or zosuquidar for six hours daily with each dose of daunorubicin. Patients will have blood samples obtained for pharmacokinetic analysis of daunorubicin and cytarabine immediately prior to the third dose of daunorubicin and for the next four days (six samples).