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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo
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Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo

机译：合成埃博霉素类似物在人骨髓瘤模型中体内外的抗肿瘤作用研究

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摘要

26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B [Flude-lone (Flu)] has shown broad antitumor activity in solid tumor models. In the present study, we showed, in vitro, that Flu significantly inhibited multiple myeloma (MM) cell proliferation (with 1-15 nM IC_(50)), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10- to 15-fold higher IC_(50)). Cell-cycle analysis demonstrated that Flu caused G_2/M phase arrest and induced cell apoptosis. After Flu treatment, caspase-3, -8, and -9 were activated, cytochrome c and second mitochondrial-derived activator of caspase were released to the cytosol, and c-Jun N-terminal kinase was activated, indicating that mitochondria were involved in the apoptosis. Flu toxicity to human hematopoietic stem cells was evaluated by CD34~+ cell-apoptosis measurements and hematopoietic-progenitor assays. There was no significant toxicity to noncycling human CD34~+ cells. We compared the efficacy of Flu with the epothilone analog 12,13-desoxyepothilone B (dEpoB) in xenograft nonobese diabetic/ severe combined immunodeficient mouse models with subcutaneous or disseminated MM. Flu caused tumor disappearance in RPMI 8226 subcutaneous xenografts after only five doses of the drug (20 mg/kg of body weight), with no sign of relapse after 100 d of observation. In a disseminated CAG MM model, mice treated with Flu had a significantly decreased tumor burden, as determined by bioluminescence imaging, and prolonged overall survival vs. mice treated with dEpoB or vehicle control, indicating that Flu may be a promising agent for MM therapy.
机译：26-三氟-（E）-9,10-脱氢-12,13-脱氧埃博霉素B [Flude-lone（Flu）]在实体肿瘤模型中显示出广泛的抗肿瘤活性。在本研究中，我们在体外显示，流感显着抑制多发性骨髓瘤（MM）细胞增殖（1-15 nM IC_（50）），而正常人骨髓基质细胞（HS-27A和HS-5系） ）具有相对抗药性（IC_（50）高10至15倍）。细胞周期分析表明，流感引起G_2 / M期停滞并诱导细胞凋亡。流感处理后，caspase-3，-8和-9被激活，细胞色素c和第二个线粒体衍生的caspase激活剂被释放到细胞质中，c-Jun N端激酶被激活，表明线粒体参与其中。凋亡。流感对人造血干细胞的毒性通过CD34〜+细胞凋亡测量和造血祖细胞测定来评估。对未循环的人CD34〜+细胞无明显毒性。我们在皮下或弥散性MM异种移植非肥胖/严重合并免疫缺陷小鼠模型中比较了Flu与埃博霉素类似物12,13-脱氧埃博霉素B（dEpoB）的疗效。仅五剂药物（20 mg / kg体重）后，流感在RPMI 8226皮下异种移植物中引起肿瘤消失，观察100天后未见复发迹象。在散布的CAG MM模型中，与用dEpoB或溶媒对照治疗的小鼠相比，通过Fluo治疗的小鼠具有显着降低的肿瘤负荷（通过生物发光成像确定），并且总体存活期延长，这表明Flu可能是有希望的MM治疗药物。

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