Antiangiogenic and antitumor activity of LP-261, a novel oral tubulin binding agent, alone and in combination with bevacizumab.
Antiangiogenic and antitumor activity of LP-261, a novel oral tubulin binding agent, alone and in combination with bevacizumab.
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DOI：
10.1007/s10637-010-9520-5
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发表时间：
2012-02
影响因子：
3.4
通讯作者：
Figg WD
中科院分区：
文献类型：
--
作者：
Gardner ER;Kelly M;Springman E;Lee KJ;Li H;Moore W;Figg WD
LP-261是一种新型的微管蛋白靶向抗癌药物，它结合于微管蛋白上的秋水仙碱部位，诱导G2/M期阻滞。对NC160癌细胞株的筛选结果显示，平均G150约为100纳米。在这里，我们报告了在多个小鼠异种移植模型和血管生成试验中的测试结果，以及生物利用度研究。为了确定LP-261的抗血管生成活性，进行了体外和体外实验。人脐静脉内皮细胞与LP-261在50 nm~10μM孵育，20 nm~10μM的大鼠主动脉环实验也检测LP-261的体内抗肿瘤活性。在结肠腺癌(SW620)和前列腺癌(LNCaP和PC3)移植瘤中，LP-261作为单一给药进行了试验，评估了几种不同的给药方案。在SW620异种移植模型中，LP-261也与贝伐单抗联合使用。LP-261还显示出高的口服生物利用度和明显缺乏肠道转运体(如ABCBI)的外流。LP-261是一种非常有效的血管生成抑制剂，在大鼠主动脉环实验中阻止微血管生长，并在纳摩尔浓度下阻止HUVEC细胞的增殖。在PC3异种移植模型中，肿瘤生长得到了完全抑制，并显示出时间依赖性。在SW620模型中观察到对肿瘤生长的良好抑制作用，与紫杉醇相当。口服低剂量LP-261与贝伐单抗联合使用可显著提高肿瘤抑制率。口服LP-261对多种小鼠异种移植瘤模型的肿瘤生长抑制非常有效，且耐受性良好。
LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NC160 cancer cell lines resulted in a mean G150 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human Umbilical Vein Endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 μM. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 μM. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCBI. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated.
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影响因子：
23.4
作者：
Di Lorenzo, Giuseppe;Figg, William D.;De Placido, Sabino
通讯作者：
De Placido, Sabino
影响因子：
78.5
作者：
Shoemaker, Robert H.
通讯作者：
Shoemaker, Robert H.
影响因子：
2.8
作者：
Lennernäs, B;Albertsson, P;Norrby, K
通讯作者：
Norrby, K
影响因子：
11.5
作者：
Burstein, Harold J.;Chen, Yu-Hui;Winer, Eric P.
通讯作者：
Winer, Eric P.
影响因子：
3.4
作者：
Sanborn, Sharon L.;Cooney, Matthew M.;Remick, Scot C.
通讯作者：
Remick, Scot C.