In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.
In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.
复制标题
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
复制
发表时间：
2005
影响因子：
5.7
通讯作者：
Baer,MariaR
中科院分区：
文献类型：
--
作者：
Minderman,Hans;Conroy,JeffreyM;O'Loughlin,KieranL;McQuaid,Devin;Quinn,Paul;Li,Song;Pendyala,Lakshmi;Nowak,NormaJ;Baer,MariaR
目标：目的研究伊立替康（CPT-11）对髓系白血病细胞周期调控和凋亡相关基因表达谱的影响。研究方法：将HL 60细胞暴露于临床可达到浓度的7-乙基-10-羟基喜树碱（SN-38）（CPT-11的活性代谢产物）和从接受CPT-11治疗的急性髓性白血病和慢性髓性白血病髓样母细胞转化患者中采集的血样。基因表达谱芯片研究基因表达的变化，并通过流式细胞术研究DNA分布与生物学反应相关。结果如下：cDNA微阵列分析显示，下调和上调特定的细胞周期相关基因，与S期细胞的损失和G1-S-期转换的暂时延迟，通过流式细胞术看到的一致。流式细胞术显示SN-38暴露期间S期细胞发生凋亡，而G2-M和G1期细胞延迟进入G1期，仅在药物去除后6 - 8小时进入S期，与观察到的基因表达变化一致。基因转录的促凋亡变化包括抗凋亡基因的下调和促凋亡基因的上调。在体外SN-38暴露后观察到的许多基因表达变化也在体内给予10或15 mg/m2 CPT-11后观察到;值得注意的是，促凋亡变化包括生存素通路相关基因转录减少和死亡受体5转录增加。结论：CPT-11诱导的体外和体内基因表达谱的变化与G1-S转换的暂时延迟和对凋亡的增强反应一致，这两者都可能有助于该药物与抗代谢药物的协同相互作用。
Objective: To study irinotecan (CPT-11)–induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cellsin vitroandin vivo. Methods: HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. Results: cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle–associated genes, consistent with loss of S-phase cells and temporary delay of G1-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G2-M and G1were delayed in G1and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed followingin vitroSN-38 exposure were also seen followingin vivoadministration of 10 or 15 mg/m2CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. Conclusion: CPT-11-induced changes in gene expression profilesin vitroandin vivoare consistent with temporary delay in G1-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.