ZOSUQUIDAR TRIHYDROCHLORIDE DURING CONVENTIONAL INDUCTION AND POST-REMISSION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。新诊断急性髓性白血病（AML）的老年人（年龄大于55岁至60岁）接受治疗的缓解率和中位总生存期分别约为50%和12个月。预后不良的主要原因是化疗耐药。一个非常明确的化疗耐药机制是多药耐药蛋白（MDR1）的药物主动外排。MDR1的表达与缓解率降低和中位总生存期相关。因此，抑制MDR1介导的外排可能改善治疗结果。盐酸佐舒魁地尔（LY335979）是一种特异性和有效的mdr1介导的外排调节剂。此外，它与柔红霉素（一种治疗AML的基本药物）的药代动力学相互作用最小。目前的临床试验需要收集和保存血浆样本，以便在安慰剂或佐苏魁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。要求GCRC支持处理全血样本。患者将不接受GCRC的方案治疗。新诊断的AML或晚期MDS患者将入住5N大学医院的保护环境病房。患者将接受常规诱导化疗（每日给予三剂量的柔红霉素，并持续输注阿糖胞苷），此外还有安慰剂或佐舒魁，每剂量柔红霉素每天6小时。在第三次给药之前和接下来的4天（6个样本），患者将获得血液样本用于柔红霉素和阿糖胞苷的药代动力学分析。

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).