Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs
Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs
复制标题
通过 mTOR 抑制剂依维莫司和抗癌药物联合治疗对 T 细胞淋巴瘤细胞进行时间表依赖性抑制
DOI：
10.1007/s10637-010-9558-4
复制
发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Lin, Tong-Yu
中科院分区：
文献类型：
--
作者：
Huang, Jia-Jia;Li, Zhi-Ming;Lin, Tong-Yu
依维莫司（RAD 001）是一种新型的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，已报道其在多种恶性肿瘤中的抗增殖活性。本研究评估了依维莫司的抗肿瘤作用和时间表依赖的协同作用与其他化疗药物在T细胞淋巴瘤细胞line.Materials和methodsHuman T细胞淋巴瘤细胞系Hut-78和Jurkat进行了治疗与剂量增加的依维莫司，单独或与多柔比星，依托泊苷，长春新碱，或硼替佐米，使用不同的给药方案。通过细胞增殖、细胞凋亡和细胞周期分布测定来测量抗肿瘤作用。药物相互作用的中位数效应analysis. ResultsEverolimus单独暴露诱导G1期细胞周期阻滞无显着的凋亡。依维莫司与多柔比星、依托泊苷和硼替佐米有协同作用，但与长春新碱有拮抗作用。多柔比星和依维莫司、硼替佐米和依维莫司、多柔比星随后依维莫司以及硼替佐米随后依维莫司联合治疗后观察到细胞毒性协同作用。相比之下，细胞暴露于依维莫司，然后是多柔比星或硼替佐米导致拮抗作用。依维莫司后序暴露于多柔比星或硼替佐米有效地防止了潜在的负面相互作用，并导致药物协同作用。药物组合的协同作用或拮抗作用与细胞周期distribution.ConclusionsEverolimus有效地抑制T细胞淋巴瘤细胞在体外的生长的可变影响。依维莫司与其他抗肿瘤药物的特定时间表依赖性组合可避免潜在的药物拮抗作用并产生有效的协同作用，可能导致T细胞淋巴瘤的临床有效治疗。
ObjectiveEverolimus (RAD001) is a novel mammalian target of rapamycin (mTOR) inhibitor, and anti-proliferative activity in various malignancies has been reported. This study evaluated the anti-tumor effects and schedule-dependent synergism of everolimus in combination with other chemotherapeutic agents in T-cell lymphoma cell lines.Materials and methodsHuman T-cell lymphoma cell lines Hut-78 and Jurkat were treated with increasing doses of everolimus, alone or in combination with doxorubicin, etoposide, vincristine, or bortezomib, using different dosing schedules. Anti-tumor effects were measured by assays for cell proliferation, apoptosis, and cell cycle distribution. Drug interactions were determined by median effect analysis.ResultsExposure to everolimus alone induced G1 phase cell cycle arrest without significant apoptosis. With certain dosing schedules, everolimus showed synergism with doxorubicin, etoposide, and bortezomib, but antagonism with vincristine. Cytotoxic synergism was observed following cotreatment with doxorubicin and everolimus, bortezomib and everolimus, doxorubicin followed by everolimus, and bortezomib followed by everolimus. By contrast, cell exposure to everolimus followed by doxorubicin or followed by bortezomib resulted in antagonistic effects. Sequential exposure to doxorubicin or bortezomib followed by everolimus effectively prevented potential negative interactions, and resulted in drug synergism. Drug combination synergisms or antagonisms were associated with variable effects on the cell cycle distribution.ConclusionsEverolimus effectively inhibited the growth of T-cell lymphoma cells in vitro. Specific schedule-dependent combinations of everolimus with other anti-tumor agents which avoid potential drug antagonism and produce effective synergism may lead to clinically effective treatments for T-cell lymphoma.