蛋白酶体抑制剂ps-341对两种小鼠肿瘤模型.docVIP

蛋白酶体抑制剂PS-341对两种小鼠肿瘤模型 （结肠癌和急性髓系白血病）治疗作用的研究 郁嘉伦，潘隽玮，沈富毅，余昂，侯晓骏 指导老师：刘玮 [摘要] 目的 研究蛋白酶体抑制剂PS-341对小鼠结肠癌和急性髓性白血病的治疗效果，并探讨其机制。方法 分别培养人结肠癌细胞LS-174-T、人急性早幼粒白血病（APL）细胞NB4及小鼠原代APL细胞，观察不同浓度的PS-341在体外抗肿瘤细胞的作用；建立小鼠结肠癌和急性髓系白血病两种肿瘤模型，于肿瘤发展的不同阶段给予PS-341治疗，观察肿瘤生长、组织器官浸润、肿瘤细胞凋亡情况，以及PS-341对小鼠生存期的影响。结果 在体外，纳摩尔浓度的PS-341能明显抑制LS-174-T、NB4及小鼠原代APL细胞的生长，并可有效诱导这三种肿瘤细胞发生凋亡。在体内，PS-341能显著抑制白血病细胞的生长和组织浸润，并明显延长白血病小鼠的生存期（P0.001）。但是，PS-341对结肠癌实体瘤的生长无抑制作用。对于白血病和实体瘤两种肿瘤模型，本研究中均未能观察到PS-341在体内诱导肿瘤细胞凋亡的作用。结论 利用同系移植的转基因白血病小鼠模型，本研究首次观察了PS-341对急性髓系白血病的体内作用及疗效。研究结果显示，无论在体外或是体内，PS-341都有显著的抗急性髓系白血病作用，这为该药应用于急性髓系白血病的治疗提供了临床前研究基础。 [关键词] PS-341，急性髓系白血病，结肠癌，治疗 [Abstract] Objective To study the therapeutic effects of PS-341 on a xenograft colon cancer mouse model and a syngraft acute promyelocytic leukemia (APL) mouse model. Methods Human colon cancer cell line LS-174-T, human APL cell line NB4 and fresh isolated mouse APL cells were cultured and treated with PS-341 at different concentrations, the effects of PS-341 on cell growth and apoptosis induction were investigated. Two mice cancer models, colon cancer and APL, were established, in vivo effects of PS-341 on tumor development, tissue invasion, apoptosis induction and mice survival were inspected. Results In vitro, nanomolar concentration of PS-341 could effectively inhibit cell growth and induce cell apoptosis in LS-174-T, NB4 and mouse APL cells. In vivo, PS-341 significantly prolongs the survival of the leukemic mice with reduced tumor invasion and progression, but it failed to inhibit the colon tumor growth in our study. In both two tumor models, we did not find the apoptosis induction actions which can be easily seen in cell culture study. Conclusions Our results showed that PS-341 had potential therapeutic effects on acute myeloid leukemia (AML). This study represents the first attempt to characterize the in vivo effects of PS-341 on an APL mouse model, and it facilitates the application of PS-341 in clinical treatment of AML. [Key words] PS-