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【Clin Cancer Res】利用MK-0457 靶向Aurora 激酶从而抑
Purpose: The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457.
Experimental Design: We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models.
Results: In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values < 0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P 0.03). Proliferating cell nuclear antigen immunohistochemistry revealed that MK-0457 alone and in combination with docetaxel significantly reduced cellular proliferation (P values < 0.001). Compared with controls, treatment with MK-0457 alone and in combination with docetaxel also significantly increased tumor cell apoptosis by 3-fold (P < 0.01). Remarkably, compared with docetaxel monotherapy, MK-0457 combined with docetaxel resulted in significantly increased tumor cell apoptosis.
Conclusions: Aurora kinase inhibition significantly reduces tumor burden and cell proliferation and increases tumor cell apoptosis in this preclinical orthotopic model of ovarian cancer. The role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.
http://clincancerres.aacrjournals.org/cgi/content/abstract/14/17/5437 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Targeting Aurora Kinase with MK-0457 Inhibits Ovarian Cancer Growth
利用MK-0457 靶向Aurora 激酶从而抑制卵巢癌的生长
Purpose: The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457.
目的：Aurora 激酶家族在保持有丝分裂完整性和细胞周期方面起着重要作用。我们将一个小的Aurora 激酶抑制剂分子-- MK-0457种植入正常小鼠体内，以观察Aurora 激酶抑制剂在抑制卵巢癌的作用。
Experimental Design: We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models.
实验设计：确定Aurora 激酶抑制剂在调控细胞周期方面的作用，并通过在体内、外单独应用Aurora 激酶抑制剂或Aurora 激酶抑制剂联合多西他赛以了解Aurora 激酶抑制剂的治疗作用。
Results: In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values < 0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P 0.03). Proliferating cell nuclear antigen immunohistochemistry revealed that MK-0457 alone and in combination with docetaxel significantly reduced cellular proliferation (P values < 0.001). Compared with controls, treatment with MK-0457 alone and in combination with docetaxel also significantly increased tumor cell apoptosis by 3-fold (P < 0.01). Remarkably, compared with docetaxel monotherapy, MK-0457 combined with docetaxel resulted in significantly increased tumor cell apoptosis.
结果：体外试验显示多西他赛对HeyA8 和SKOV3ip1细胞的毒性是多西他赛联合MK-0457的10倍以上。体内试验中，通过测定磷酸化组蛋白H3水平来了解剂量动力学。HeyA8 和SKOV3ip1对Aurora 激酶抑制剂敏感性试验及HeyA8-MDR 和A2780-CP20对Aurora 激酶抑制剂抵抗性试验结果显示与对照组相比Aurora 激酶抑制剂可以显著降低肿瘤负荷(P < 0.01)。联合多西他赛治疗方案与单独应用多西他赛方案相比，可以显著降低肿瘤生长(P= 0.03)。增生细胞核抗原的免疫组化检查显示MK-0457以及MK-0457联合多西他赛可以显著减少细胞增生(P < 0.001)。与对照组相比，MK-0457以及MK-0457联合多西他赛均可使肿瘤细胞凋亡增加3倍(P < 0.01)。与单独使用多西他赛相比，MK-0457联合多西他赛可以显著增加肿瘤细胞凋亡。
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作者:admin@医学,生命科学 2011-03-27 11:48
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