Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma.
Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma.
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DOI：
10.1038/sj.bjc.6604388
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发表时间：
2008-06-17
影响因子：
8.8
通讯作者：
Vanderkerken, K.
中科院分区：
文献类型：
--
作者：
Caers, J.;Menu, E.;De Raeve, H.;Lepage, D.;Van Valckenborgh, E.;Van Camp, B.;Alvarez, E.;Vanderkerken, K.
Aplidin®是一种抗肿瘤药物，目前正在不同的血液和实体肿瘤中进行II期评估。在这项研究中，我们分析了Aplidin在同基因5 T33 MM模型中的抗骨髓瘤作用，该模型可代表人类疾病。在体外，Aplidin抑制5 T33 MMvv DNA合成，IC 50为3.87 nM。在细胞周期进程中，药物诱导细胞从G 0/G1期向S期转变，而Western blot显示细胞周期蛋白D1和CDK 4表达下降。此外，Aplidin通过降低线粒体膜电位、诱导细胞色素C释放和激活半胱天冬酶-9和半胱天冬酶-3诱导细胞凋亡。对于体内实验，用媒介物或Aplidin（每天90 μg kg-1）腹膜内处理5 T33 MM注射的C57 Bl/KaLwRij小鼠。Aplidin长期治疗耐受性良好，血清副蛋白浓度降低42%（P<0.001），而骨髓瘤细胞的BM侵袭降低35%（P<0.001）。Aplidin还将骨髓瘤相关的血管生成降低至基础值。这种抗血管生成作用在体外得到证实，并通过抑制内皮细胞增殖和血管形成来解释。这些数据表明，Aplidin在体内耐受性良好，其抗肿瘤和抗血管生成作用支持该药物在多发性骨髓瘤中的使用。
Aplidin® is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC50 of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 μg kg−1 daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
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影响因子：
8.8
作者：
Manning, L S;Berger, J D;O'Donoghue, H L;Sheridan, G N;Claringbold, P G;Turner, J H
通讯作者：
Turner, J H
影响因子：
2.1
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Avet-Loiseau, H
影响因子：
20.3
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Kröger, N;Sayer, HG;Zander, AR
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影响因子：
8
作者：
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通讯作者：
Kuehl, WM
影响因子：
4.8
作者：
Gajate, C;Mollinedo, F
通讯作者：
Mollinedo, F