Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
Mol Cancer Ther. 2010 May;9(5):1128-35. doi: 10.1158/1535-7163.MCT-10-0096. Epub 2010 Apr 20.
Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo. In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects.
达沙替尼是一种口服的多靶点激酶抑制剂，可靶向Src 家族酪氨酸激酶、Abl、c-Kit 和 PDGFR。进行了一项临床前研究，以评估达沙替尼单药或联合顺铂治疗人移行细胞癌（TCC）。通过免疫组织化学评估人 TCC 组织微阵列中Src 的表达。评估了六种人 TCC 细胞系中达沙替尼和/或顺铂的活性。进行 Western blot 以评估 Src 和磷酸化-Src（p-Src）的表达。评估了达沙替尼单药和联合顺铂在鼠皮下异种移植中的活性。62%至 75%的人 TCC 表达 Src。达沙替尼在纳摩尔浓度下对两种人 TCC 细胞系（RT4 和 Hu456）显示出显著的抗增殖活性，这两种细胞系表现出高 Src 和 p-Src 表达，并且对顺铂耐药。RT4 细胞最敏感，显示出最高水平的 Src 途径激活（p-Src/Src 比值）。达沙替尼下调敏感或耐药细胞中的 p-Src。对顺铂敏感的 TCC 细胞（5637 和 TCC-SUP）对达沙替尼高度耐药，并且表达低水平的 Src。达沙替尼在 RT4 鼠异种移植中显示出抗肿瘤活性，达沙替尼联合顺铂的组合比安慰剂更具活性。联合达沙替尼加顺铂显著抑制体内增殖并促进凋亡。总之，达沙替尼对 Src 过表达的人 TCC 显示出显著的临床前抗肿瘤活性，并且在体内与顺铂联合具有高度活性。在选定的人类受试者中可能需要进一步的临床开发。
