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替沃扎尼，一种用于实体瘤潜在治疗的泛血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂。

Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors.

作者信息

De Luca Antonella, Normanno Nicola

机构信息

INT-Fondazione Pascale, Cell Biology and Biotherapy Unit, Via Mariano Semmola, Naples, Italy.

出版信息

IDrugs. 2010 Sep;13(9):636-45.

PMID:20799147
Abstract

Tivozanib (AV-951; KRN-951), being developed by AVEO Pharmaceuticals Inc and Kyowa Hakko Kirin Co Ltd, is an orally active, ATP-competitive, small-molecule, quinoline-urea derivative that inhibits VEGFR tyrosine kinase for the potential treatment of cancer. In particular, tivozanib is able to markedly inhibit the ligand-induced phosphorylation of VEGFR-1, VEGFR-2 and VEGFR-3 at picomolar concentrations. In preclinical studies, tivozanib produced a significant inhibition of tumor growth and angiogenesis in several different xenograft tumor models in athymic rats. In a phase I clinical trial, tivozanib was safe and tolerable when administered at oral doses up to 1.5 mg on a schedule of 4 weeks on, 2 weeks off treatment. Results from a phase II clinical trial in patients with advanced renal cell carcinoma reported an overall response rate of 25.4% and a median progression-free survival of 11.8 months in patients treated with tivozanib as a single agent. Hypertension and dysphonia were the most frequent adverse events. At the time of publication, a phase III clinical trial was recruiting patients with advanced renal cancer to assess tivozanib in comparison with sorafenib. Clinical trials are currently ongoing to evaluate the safety and antitumor activity of tivozanib in breast, lung and colorectal cancer. Tivozanib might represent a promising anticancer agent in several different tumor types.

摘要

替沃扎尼（AV-951；KRN-951）由AVEO制药公司和日本协和麒麟株式会社联合研发，是一种口服活性、ATP竞争性、小分子喹啉脲衍生物，可抑制VEGFR酪氨酸激酶，具有潜在的癌症治疗作用。特别是，替沃扎尼能够在皮摩尔浓度下显著抑制配体诱导的VEGFR-1、VEGFR-2和VEGFR-3磷酸化。在临床前研究中，替沃扎尼在无胸腺大鼠的几种不同异种移植肿瘤模型中对肿瘤生长和血管生成产生了显著抑制作用。在一项I期临床试验中，替沃扎尼按4周用药、2周停药的方案口服给药，剂量高达1.5mg时安全且耐受性良好。一项针对晚期肾细胞癌患者的II期临床试验结果显示，接受替沃扎尼单药治疗的患者总缓解率为25.4%，中位无进展生存期为11.8个月。高血压和发音困难是最常见的不良事件。在发表时，一项III期临床试验正在招募晚期肾癌患者，以评估替沃扎尼与索拉非尼相比的疗效。目前正在进行临床试验，以评估替沃扎尼在乳腺癌、肺癌和结直肠癌中的安全性和抗肿瘤活性。替沃扎尼可能是几种不同肿瘤类型中一种有前景的抗癌药物。

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Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors.替沃扎尼，一种用于实体瘤潜在治疗的泛血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂。
IDrugs. 2010 Sep;13(9):636-45.
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Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.在晚期实体瘤患者中，采用每周给药 4 周、停药 2 周的方案，评估血管内皮生长因子受体-1、-2 和-3 酪氨酸激酶选择性抑制剂替沃扎尼（AV-951，KRN-951）的生物学和临床活性。
Clin Cancer Res. 2011 Nov 15;17(22):7156-63. doi: 10.1158/1078-0432.CCR-11-0411. Epub 2011 Oct 5.
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Tivozanib for the treatment of renal cell carcinoma: results and implications of the TIVO-1 trial.替沃扎尼治疗肾细胞癌：TIVO-1试验的结果及意义
Future Oncol. 2014 Aug;10(11):1819-26. doi: 10.2217/fon.14.120.
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The role of tivozanib in advanced renal cell carcinoma therapy.替沃扎尼布在晚期肾细胞癌治疗中的作用。
Expert Rev Anticancer Ther. 2018 Nov;18(11):1113-1124. doi: 10.1080/14737140.2018.1508348. Epub 2018 Aug 21.
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A highly selective, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor has potent activity in vitro and in vivo.一种高选择性、口服生物利用度的血管内皮生长因子受体-2 酪氨酸激酶抑制剂，具有强大的体外和体内活性。
Angiogenesis. 2009;12(3):287-96. doi: 10.1007/s10456-009-9151-7. Epub 2009 Jun 21.
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Tivozanib: practical implications for renal cell carcinoma and other solid tumors.替沃扎尼：对肾细胞癌及其他实体瘤的实际意义。
Drugs Today (Barc). 2013 May;49(5):303-15. doi: 10.1358/dot.2013.49.5.1960218.
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Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma.在一项评估肾细胞癌患者抗肿瘤活性和安全性的 II 期随机停药试验中，替沃扎尼（AV-951）的表现。
J Clin Oncol. 2012 May 10;30(14):1678-85. doi: 10.1200/JCO.2011.35.3524. Epub 2012 Apr 9.
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Structure, development, preclinical and clinical efficacy of tivozanib (KRN-951, AV-951).替沃扎尼（KRN-951，AV-951）的结构、研发、临床前及临床疗效。
Future Oncol. 2013 Jan;9(1):13-20. doi: 10.2217/fon.12.167.
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A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer.盐酸替沃扎尼联合每周紫杉醇治疗转移性乳腺癌的 I 期剂量递增研究。
Breast Cancer Res Treat. 2013 Jul;140(2):331-9. doi: 10.1007/s10549-013-2632-9. Epub 2013 Jul 19.
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Tivozanib for the treatment of metastatic renal cancer.替沃扎尼布治疗转移性肾细胞癌。
Expert Rev Anticancer Ther. 2013 Jun;13(6):649-60. doi: 10.1586/era.13.40.

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