Cytokinetics, Inc., South San Francisco, California 94080, USA.
Clin Cancer Res. 2010 Jan 15;16(2):566-76. doi: 10.1158/1078-0432.CCR-09-1498. Epub 2010 Jan 12.
Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.
We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.
In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.
These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.
伊匹尼司他（SB-715992）是一种有效的驱动蛋白纺锤体蛋白抑制剂，该蛋白是形成双极有丝分裂纺锤体和通过有丝分裂进行细胞周期进展所必需的驱动蛋白运动蛋白。伊匹尼司他的临床研究表明，局部晚期或转移性乳腺癌患者的反应率为 9%，且具有良好的安全性特征，没有明显的神经毒性、胃肠道毒性或脱发。为了更好地了解伊匹尼司他在乳腺癌治疗中的潜力，我们研究了伊匹尼司他单独使用和与几种已批准用于治疗乳腺癌的疗法联合使用的活性。
我们在体外测量了代表各种亚型的乳腺癌细胞系的伊匹尼司他敏感性和药效反应，并在体内作为异种移植物进行了测试，还测试了伊匹尼司他增强已批准疗法抗肿瘤活性的能力。
在体外，伊匹尼司他对 53 种乳腺癌细胞系的增殖显示出广泛的抑制活性。在体内，伊匹尼司他在五种乳腺癌模型中的每一种中都产生了消退，并在其中三种模型中产生了无肿瘤存活者。在体外和体内检查了伊匹尼司他治疗对有丝分裂和细胞凋亡药效标志物的影响，结果表明 MDA-MB-468 模型中两种有丝分裂和凋亡标志物的增加均大于敏感性较低的 BT-474 模型。在体内，伊匹尼司他增强了曲妥珠单抗、拉帕替尼、多柔比星和卡培他滨的抗肿瘤活性，并表现出与紫杉醇和伊沙匹隆相当的活性。
这些发现支持进一步探索驱动蛋白纺锤体蛋白抑制剂治疗乳腺癌的临床应用。
