IRINOTECAN AND CYTARABINE IN ACUTE MYELOID LEUKEMIA

伊立替康和阿糖胞苷治疗急性髓系白血病

• 批准号: 6378210
• 负责人: MARIA R BAER
• 金额: $ 27.23万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378210
• 关键词: DNA topoisomerases; acute myelogenous leukemia; carboxylic ester hydrolases; chemical models; clinical research; combination chemotherapy; cytosine arabinoside; drug resistance; enzyme activity; human subject; human therapy evaluation; irinotecan; model design /development; neoplasm /cancer chemotherapy; pharmacokinetics

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.

急性髓样白血病（AML）的治疗结果有所改善， AML。为了改善AML的治疗结果，迫切需要 开发攻击新型细胞靶标，而不是 受已知抗性机制的影响。 Irinotecan（CPT-11）是 拓扑异构酶I I-Interactive药物，作为单一药物，已显示有限 针对5-氯酸（5-FU） - 性交结直肠癌的活性，但在 与5-FU的结合，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 高度依赖于计划。我们发现CPT-11高度活跃 体内耐多药的人白血病异种移植。而且，临床前 来自我们实验室的数据表明，与时间表有关的协同作用 发现CPT-11和5-FU的药物相互作用也适用于 CPT-11与ARA-C结合使用。基于这些临床前发现，一个阶段 I临床方案的设计和启动将CPT-11与ARA-C组合在一起 在髓样中的难治性AML和慢性粒细胞性白血病的治疗 爆炸转化（CML-MBT）。该应用的目的是开发 CPT-11和ARA-C组合化疗作为髓样白血病的治疗 对当前疗法有抵抗力；然后这种方法随后将是 应用于未经处理的AML，对当前方案的反应可能性很小。 提出的具体目的是：1。定义CPT-11和ARA-C的功效 难治性AML和CML-MBT中的联合化疗； 2。优化 基于实验室的CPT-11和ARA-C组合化疗的时间表 功效的相关性； 3。确定灵敏度的相关性和 对CPT-11和ARA-C组合化疗的抗性。

项目成果

Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function.

急性髓系白血病中的乳腺癌耐药蛋白（BCRP/MXR/ABCG2）：表达与功能之间的不一致。

• DOI: 10.1038/sj.leu.2403395
• 发表时间: 2004
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Suvannasankha,A;Minderman,H;O'Loughlin,KL;Nakanishi,T;Greco,WR;Ross,DD;Baer,MR
• 通讯作者: Baer,MR

In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.

体外和体内伊立替康诱导急性髓系白血病细胞细胞周期和凋亡相关基因表达谱的变化。

• DOI: 10.1158/1535-7163.mct-04-0048
• 发表时间: 2005
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Minderman,Hans;Conroy,JeffreyM;O'Loughlin,KieranL;McQuaid,Devin;Quinn,Paul;Li,Song;Pendyala,Lakshmi;Nowak,NormaJ;Baer,MariaR
• 通讯作者: Baer,MariaR