Department of Pharmacology, Array BioPharma Inc., Boulder, CO 80301, USA.
Anticancer Res. 2009 Nov;29(11):4373-80.
Profiling the efficacy and pharmacodynamic activity of the kinesin spindle protein (KSP) inhibitor ARRY-520 will aid the identification of responsive tumor types and pharmacodynamic profiles that correlate with activity.
In vivo activity was evaluated in a diverse panel of 16 different tumor xenograft models. Pharmacodynamic activity was evaluated in selected models.
ARRY-520 had low nanomolar antiproliferative activity in tumor cell lines. Monopolar spindles were formed at active potencies. Partial or complete responses were observed in 13/16 xenograft models. Hematological tumors were particularly sensitive, with a 100% complete response rate in some models. Maintenance of mitotic block for a sufficient length of time for cells to lose survival signals and progress to apoptosis was a key component of the mechanism of activity. ARRY-520 was also active in several taxane resistant models.
The data provide a rationale for clinical evaluation of the activity of ARRY-520 in hematological carcinomas and taxane-resistant tumors.
分析驱动蛋白纺锤体蛋白（KSP）抑制剂 ARRY-520 的疗效和药效学活性，将有助于确定与活性相关的敏感肿瘤类型和药效学特征。
在 16 种不同的肿瘤异种移植模型的多样化小组中评估体内活性。在选定的模型中评估药效学活性。
ARR-520 在肿瘤细胞系中具有低纳摩尔级的抗增殖活性。在有效浓度下形成单极纺锤体。在 16 个异种移植模型中的 13 个中观察到部分或完全反应。血液系统肿瘤特别敏感，在一些模型中完全反应率为 100%。维持有丝分裂阻断足够长的时间，使细胞失去生存信号并进展为细胞凋亡，这是活性机制的关键组成部分。ARR-520 在几种紫杉烷耐药模型中也具有活性。
这些数据为评估 ARRY-520 在血液系统恶性肿瘤和紫杉烷耐药肿瘤中的活性提供了依据。
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