人MDS荷瘤小鼠模型的建立及砷剂、沙利度胺在荷瘤小鼠体内抗瘤作用与机制的研究

发布时间：2018-06-21 16:16

本文选题：骨髓增生异常综合症 + 细胞株　；参考：《浙江大学》2005年博士论文

【摘要】：骨髓增生异常综合征(myelodysplastic syndromes,MDS)是一组起源于造血干/祖细胞的恶性克隆性疾病,以骨髓病态造血、外周血细胞减少及高风险转化为急性髓细胞性白血病(acute myelocytic leukaemia,AML)为主要特征。迄今MDS的发病机制不明,仍无标准有效的治疗方案。因此,迫切需要寻找新的有效的治疗药物。三氧化二砷(arsenic trioxide,ATO),是目前研究的热点之一。多年来ATO用于治疗初发或复发难治性急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)疗效显著;ATO治疗APL至少通过两种机制:一种是降解融合蛋白PML RARa,去除它对网络信号传导和诱导分化的负性抑制作用,另一种是诱导细胞凋亡。而ATO治疗MDS的疗效报道不一,其机制不明。沙利度胺(Thalidomide,THAL)曾经是治疗妊娠反应的老药,近年来由于它的免疫调节、抗炎、抗肿瘤等作用又重新用于临床,治疗多发性骨髓瘤和部分实体瘤获得较满意的效果。CC5013(为Thalidomide的类似物)治疗MDS 5q-患者疗效明显,但其机制不清楚。研究疾病发病机理和筛选治疗药物的最好载体之一是动物模型,迄今国内外未见有成功建立MDS动物模型的文献报道。我们试图通过建立人MDS荷瘤小鼠模型,以探讨ATO、THAL单用及联用治疗在MDS荷瘤小鼠的体内抗瘤作用及其机制,为临床治疗MDS病人提供新的思路和理论依据。
[Abstract]:Myelodysplastic syndrome (MDS) is a group of malignant clonal diseases originating from hematopoietic stem / progenitor cells. Myelodysplastic syndrome is characterized by morbid hematopoiesis, decreased peripheral blood cells and high risk of acute myelocytic leukemia. So far, the pathogenesis of MDS is unknown, and there is still no standard and effective treatment. Therefore, there is an urgent need to find new and effective treatment drugs. Arsenic trioxide (as _ 2O _ 3) is one of the hotspots in recent years. Over the years, ATO has been used in the treatment of acute promyelocytic leukemia (promyelocytic). The effect of ATO on acute promyelocytic leukemia (promyelocytic) is at least two mechanisms: one is to degrade the fusion protein, PML RaRaa, and to remove it from network signal transduction and induction. The negative inhibitory effect of differentiation, The other is to induce apoptosis. However, the therapeutic effect of ATO on MDS is not reported, and its mechanism is unclear. Thalidomide Thalidomide THALA was once an old drug for the treatment of pregnancy response, and has been reused in clinic in recent years due to its immunomodulation, anti-inflammatory and anti-tumor effects. Satisfactory results were obtained in the treatment of multiple myeloma and some solid tumors. CC5013 (a Thalidomide analogue) was effective in the treatment of MDS 5q- patients, but the mechanism was not clear. The animal model is one of the best carriers for studying the pathogenesis of disease and screening the drug for treatment. So far, there have been no reports on the successful establishment of MDS animal model at home and abroad. We try to establish human MDS tumor-bearing mice model to explore the anti-tumor effect and its mechanism of ATOTHAL alone and combined therapy in MDS mice, and to provide new ideas and theoretical basis for clinical treatment of MDS patients.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R551.3;R-332

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