IRINOTECAN AND CYTARABINE IN ACUTE MYELOID LEUKEMIA

急性髓系白血病(AML)的治疗结果有所改善， AML。为了改善急性髓细胞白血病的治疗结果，迫切需要 开发攻击新细胞靶点的治疗方法，而不是 受已知抗药性机制的影响。伊立替康(CPT-11)是一种 拓扑异构酶I相互作用药物，作为单一药物，已显示出有限的 对5-氟尿嘧啶(5-FU)耐药结直肠癌的活性，但在 与5-FU联合使用，对治疗该病非常有效 临床前模型和临床试验中。这种组合的效果是 高度依赖于日程安排。我们发现CPT-11具有很强的抗病毒活性 体内多药耐药人白血病异种移植瘤。此外，临床前 我们实验室的数据表明，依赖于时间表的协同效应 已发现的CPT-11和5-FU的药物相互作用也适用于 CPT-11与Ara-C联合应用。基于这些临床前研究结果，一个阶段 I临床方案由CPT-11和Ara-C联合设计和启动 难治性急性髓系白血病和慢性髓系白血病的治疗 BLAST变换(CML-MBT)。此应用程序的目标是开发 CPT-11联合Ara-C方案治疗髓系白血病 抵抗当前的治疗方法；这种方法随后将是 适用于对当前方案有低反应可能性的未经治疗的AML。 提出的具体目标是：1.确定CPT-11和Ara-C的疗效 联合化疗治疗难治性AML和CML-MBT；2.优化方案 基于实验室的CPT-11和Ara-C联合化疗方案 与疗效的相关性；以及3.确定敏感性和 对CPT-11和Ara-C联合化疗耐药。

Treatment outcome has improved in acute myeloid leukemia (AML), AML. To improve treatment outcomes in AML, there is a compelling need to develop treatments which attack novel cellular targets and which are not affected by known mechanisms of resistance. Irinotecan (CPT-11) is a topoisomerase I-interactive drug which, as a single agent, has shown limited activity against 5-florouracil (5-FU)-refractory colorectal cancer, but, in combination with 5-FU, is very effective against the disease both in preclinical models and in clinical trials. The efficacy of this combination is highly schedule-dependent. We have found that CPT-11 is highly active against multidrug-resistant human leukemia xenografts in vivo. Moreover, preclinical data from our laboratory demonstrate that the schedule-dependent synergistic drug interaction which has been found for CPT-11 and 5-FU also applies to CPT-11 in combination with Ara-C. Based on these preclinical findings, a Phase I clinical protocol was designed and initiated combining CPT-11 with Ara-C in the treatment of refractory AML and chronic myelogenous leukemia in myeloid blast transformation (CML-MBT). The objective of this application is to develop CPT-11 and Ara-C combination chemotherapy as a treatment for myeloid leukemias resistant to current therapies; this approach would then subsequently be applied to untreated AML with a low likelihood of response to current regimens. The specific aims presented are: 1. To define the efficacy of CPT-11 and Ara-C combination chemotherapy in refractory AML and in CML-MBT; 2. To optimize the schedule of CPT-11 and Ara-C combination chemotherapy based on laboratory correlates of efficacy; and 3. To identify correlates of sensitivity and resistance to CPT-11 and Ara-C combination chemotherapy.