IRINOTECAN AND CYTARABINE IN ACUTE MYELOID LEUKEMIA

急性髓性白血病（AML）的治疗结果有所改善， 急性髓细胞白血病为了改善AML的治疗结果，迫切需要 开发攻击新的细胞靶点的治疗方法， 受到已知的抵抗机制的影响。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， 对5-氟尿嘧啶（5-FU）难治性结直肠癌的活性，但在 与5-FU联合使用，对疾病非常有效， 临床前模型和临床试验。这种组合的功效是 高度依赖于时间表。我们已经发现CPT-11对抗 体内多药耐药人白血病异种移植物。此外，临床前 我们实验室的数据表明， CPT-11和5-FU的药物相互作用也适用于 CPT-11联合Ara-C。基于这些临床前发现， 设计并启动了CPT-11与Ara-C联合治疗的I期临床方案， 难治性AML和慢性粒细胞白血病的治疗 胚细胞转化（CML-MBT）。该应用程序的目标是开发 CPT-11联合阿糖胞苷治疗髓系白血病 对目前的疗法有抗性;这种方法随后将被 适用于对当前方案反应可能性低的未经治疗的AML。 提出的具体目标是：1。确定CPT-11和Ara-C的疗效 难治性AML和CML-MBT的联合化疗; 2.优化 CPT-11和阿糖胞苷联合化疗方案基于实验室 功效的相关性;以及3.识别敏感性和 CPT-11和Ara-C联合化疗的耐药性。

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.