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.

急性髓系白血病 (AML) 的治疗结果有所改善， 反洗钱。为了改善 AML 的治疗效果，迫切需要 开发攻击新细胞靶标的治疗方法 受已知耐药机制的影响。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 对抗 5-氟尿嘧啶 (5-FU) 难治性结直肠癌的活性，但是， 与 5-FU 联合使用，对以下疾病非常有效 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。我们发现 CPT-11 对 体内多重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，依赖于时间表的协同作用 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 组合。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 相结合 难治性 AML 和慢性粒细胞白血病的治疗 急变转化（CML-MBT）。该应用程序的目标是开发 CPT-11 和 Ara-C 联合化疗治疗髓系白血病 对现有疗法有抵抗力；这种方法随后将是 适用于未经治疗的 AML，对当前治疗方案产生反应的可能性较低。 提出的具体目标是： 1. 确定 CPT-11 和 Ara-C 的功效 难治性 AML 和 CML-MBT 的联合化疗； 2. 优化 基于实验室的CPT-11和Ara-C联合化疗方案 功效的相关性； 3. 确定敏感性和 对 CPT-11 和 Ara-C 联合化疗耐药。

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