Sonpavde Guru, Jian Weiguo, Liu Hao, Wu Meng-Fen, Shen Steven S, Lerner Seth P
Texas Oncology, P.A. and U.S. Oncology Research, Houston, TX 77030, USA.
Urol Oncol. 2009 Jul-Aug;27(4):391-9. doi: 10.1016/j.urolonc.2008.03.017. Epub 2008 Jun 4.
Sunitinib malate (Pfizer, Inc.) is a multitargeted kinase inhibitor that inhibits vascular endothelial growth factor (VEGF) receptor (R)-1, 2 and 3, platelet-derived growth factor receptors (PDGFR)-alpha and beta, Flt3, RET, and Kit. Angiogenesis and VEGF expression correlate with poor outcomes in human urothelial carcinoma. We designed a preclinical study to examine the efficacy of sunitinib alone and in combination with cisplatin against human urothelial carcinoma.
The in vitro activities of sunitinib and cisplatin alone and in combination were determined against human urothelial carcinoma cell lines, TCC-SUP and 5637. Antitumor activities were also determined in vivo against murine subcutaneous 5637 xenografts. Immunohistochemistry (IHC) was performed to detect VEGFR2 and Kit, and modulation of proliferation, apoptosis, and angiogenesis.
Both cell lines expressed VEGFR2, but did not express Kit. Sunitinib displayed activity against both cell lines in vitro at low micromolar concentrations, which are not attainable in vivo, and was synergistic with cisplatin. Activity was observed for sunitinib at 20 and 40 mg/kg orally once daily for 4 weeks, which attains low nanomolar concentrations in vivo against murine 5637 xenografts. Sunitinib 20 mg/kg/d in combination with cisplatin 4 mg/kg/wk intraperitoneally induced tumor regression compared to no therapy (P < 0.0001) or cisplatin alone (P = 0.06). Cisplatin, sunitinib, and combination treated tumors displayed significantly reduced ki-67 expression compared with control untreated tumors, and the difference was also statistically significant for the combination compared with cisplatin. Cleaved caspase-3 expression was significantly higher for sunitinib single agent and combination therapy compared with untreated controls, and for combination therapy compared with cisplatin alone. CD31 expression was diminished for both single agents and combination therapy compared with untreated tumors.
Sunitinib is preclinically active against urothelial carcinoma, and enhances the activity of cisplatin probably by targeting the stroma.
苹果酸舒尼替尼（辉瑞公司）是一种多靶点激酶抑制剂，可抑制血管内皮生长因子（VEGF）受体（R）-1、2和3、血小板衍生生长因子受体（PDGFR）-α和β、Flt3、RET和Kit。血管生成和VEGF表达与人类尿路上皮癌的不良预后相关。我们设计了一项临床前研究，以研究舒尼替尼单独及与顺铂联合应用对人类尿路上皮癌的疗效。
测定舒尼替尼和顺铂单独及联合应用对人类尿路上皮癌细胞系TCC-SUP和5637的体外活性。还在体内测定了对小鼠皮下5637异种移植瘤的抗肿瘤活性。进行免疫组织化学（IHC）检测VEGFR2和Kit，以及增殖、凋亡和血管生成的调节。
两种细胞系均表达VEGFR2，但不表达Kit。舒尼替尼在低微摩尔浓度下对两种细胞系均显示出体外活性，这种浓度在体内无法达到，且与顺铂具有协同作用。观察到舒尼替尼以20和40mg/kg口服，每日一次，持续4周，在体内对小鼠5637异种移植瘤可达到低纳摩尔浓度。与未治疗（P<0.0001）或单独使用顺铂（P=0.06）相比，舒尼替尼20mg/kg/d联合顺铂4mg/kg/周腹腔注射可诱导肿瘤消退。与未治疗的对照肿瘤相比，顺铂、舒尼替尼和联合治疗的肿瘤显示ki-67表达显著降低，联合治疗与顺铂相比差异也具有统计学意义。与未治疗的对照相比，舒尼替尼单药和联合治疗的裂解型半胱天冬酶-3表达显著更高，联合治疗与单独使用顺铂相比也更高。与未治疗的肿瘤相比，单药和联合治疗的CD31表达均降低。
舒尼替尼在临床前对尿路上皮癌具有活性，可能通过靶向基质增强顺铂的活性。
