期刊
CANCER MEDICINE
卷 5, 期 11, 页码 3031-3040出版社
WILEY-BLACKWELL
DOI: 10.1002/cam4.845
关键词
Cox-1; Cox-4; mitochondrial protein synthesis; pharmacodynamics; pharmacokinetics
类别
资金
- Ontario Institute of Cancer Research
- Ontario Ministry of Research and Innovation, National Institutes of Health (NCI) [1R01CA157456]
- Leukemia and Lymphoma Society
- MaRS Innovation
- Canadian Stem Cell Network
- Trillium Therapeutics
- Princess Margaret Cancer Centre Foundation
- Ministry of Long Term Health and Planning in the Province of Ontario
- NCI [P30 CA 168524]
Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50-350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half-life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据