Preclinical evaluation of the novel multi-targeted agent R1530
Preclinical evaluation of the novel multi-targeted agent R1530
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DOI：
10.1007/s00280-011-1608-x
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发表时间：
2011-12-01
影响因子：
3
通讯作者：
Higgins, Brian
中科院分区：
文献类型：
--
作者：
Kolinsky, Kenneth;Tovar, Christian;Higgins, Brian
本研究描述了多激酶抑制剂R1530的体外抗增殖活性、体内抗肿瘤和抗血管生成活性、药代动力学和耐受性。研究了R1530在人肿瘤、内皮细胞和成纤维细胞中的抗增殖活性。在移植了多种人类肿瘤的小鼠中，对其耐受性和抗肿瘤活性进行了评估，并在小鼠角膜袋实验中建立了抗血管生成特性。建立R1530在小鼠体内的药动学。R1530对人肿瘤细胞增殖有较强的抑制作用。生长因子驱动的内皮细胞和成纤维细胞的增殖也受到抑制。在肺癌异种移植瘤模型中，R1530 （3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw）的剂量范围显示出显著的肿瘤生长抑制作用。日剂量在肺癌模型中最有效，在结直肠癌、前列腺癌和乳腺肿瘤模型中也有显著的生长抑制作用。使用最大耐受日剂量（50 mg/kg）治疗的所有模型均出现肿瘤消退。25和50 mg/kg qd剂量可显著提高所有模型的存活率。裸鼠口服后，R1530表现出良好的组织穿透性。口服给药剂量依赖于100mg /kg。R1530在体外和体内已经证明对一系列肿瘤模型具有活性，并且是一种有效的血管生成抑制剂。这些发现支持针对多种途径寻找具有改善抗癌特性的潜在药物的方法。
This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo.The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established.R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration.R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties.