Wilkinson Robert W, Odedra Rajesh, Heaton Simon P, Wedge Stephen R, Keen Nicholas J, Crafter Claire, Foster John R, Brady Madeleine C, Bigley Alison, Brown Elaine, Byth Kate F, Barrass Nigel C, Mundt Kirsten E, Foote Kevin M, Heron Nicola M, Jung Frederic H, Mortlock Andrew A, Boyle F Thomas, Green Stephen
AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Clin Cancer Res. 2007 Jun 15;13(12):3682-8. doi: 10.1158/1078-0432.CCR-06-2979.
In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B).
The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes.
AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to > or =100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment.
These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.
在本研究中，我们检测了新型特异性极光激酶活性抑制剂AZD1152（对极光激酶B具有选择性）的体内效应。
在一组人肿瘤异种移植模型中确定AZD1152的药效学效应和疗效。AZD1152通过几种非肠道途径（皮下渗透微型泵、腹腔注射和静脉注射）给药。
在免疫缺陷小鼠中，AZD1152有效抑制了人结肠、肺和血液肿瘤异种移植瘤的生长（平均肿瘤生长抑制范围为55%至≥100%；P<0.05）。对经静脉注射AZD1152治疗的携带结肠直肠癌SW620肿瘤的无胸腺大鼠进行详细的药效学分析，结果显示肿瘤中出现了一系列表型事件：组蛋白H3磷酸化短暂抑制，随后细胞中4N DNA积累（比对照组高2.4倍），然后多倍体细胞比例增加（>4N DNA，比对照组高2.3倍）。组织学分析显示，在AZD1152治疗的肿瘤中，异常细胞分裂与细胞凋亡增加同时出现。骨髓分析显示，该药物可导致短暂的骨髓抑制，在停止AZD1152治疗后可完全逆转。
这些数据表明，选择性靶向极光激酶B可能是治疗一系列恶性肿瘤的一种有前景的治疗方法。除了抑制组蛋白H3磷酸化外，肿瘤细胞多倍体和凋亡的测定可能是这类治疗药物有用的生物标志物。AZD1152目前正处于I期试验阶段。
