Emanuel Stuart, Gruninger Robert H, Fuentes-Pesquera Angel, Connolly Peter J, Seamon Jennifer A, Hazel Susan, Tominovich Rose, Hollister Beth, Napier Cheryl, D'Andrea Michael R, Reuman Michael, Bignan Gilles, Tuman Robert, Johnson Dana, Moffatt David, Batchelor Mark, Foley Anne, O'Connell James, Allen Rodger, Perry Martin, Jolliffe Linda, Middleton Steven A
Johnson and Johnson Pharmaceutical Research and Development, 1000 Route 202, Raritan, NJ 08869, USA.
Mol Pharmacol. 2004 Sep;66(3):635-47. doi: 10.1124/mol.104.000638.
Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 microM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.
抑制血管生成在癌症治疗中可能有广泛应用；然而，仅采用这种方法不会使肿瘤消退，而可能只会减缓实体瘤的生长。将抗血管生成药物与传统化疗药物联合使用，可能会提高其临床应用潜力。4-[4-(1-氨基-1-甲基乙基)phenyl]-2-[4-(2-吗啉-4-基-乙基)phenylamino]嘧啶-5-腈（JNJ-17029259）代表了一类新型结构的5-氰基嘧啶，它们口服可用，是血管内皮生长因子受体-2（VEGF-R2）以及其他参与血管生成的酪氨酸激酶（如血小板衍生生长因子受体、成纤维细胞生长因子受体、VEGF-R1和VEGF-R3）的选择性纳摩尔抑制剂，但对其他激酶家族活性很小。在纳摩尔水平，JNJ-17029259可阻断人内皮细胞中VEGF刺激的丝裂原活化蛋白激酶信号传导、增殖/迁移以及VEGF-R2磷酸化；在大鼠主动脉环血管生成模型中抑制血管芽生的形成；并在绒毛尿囊膜试验中干扰新静脉和动脉的发育。在1至3 microM的较高浓度下，该化合物对细胞具有抗增殖活性，这可能有助于其抗肿瘤作用。当作为单药疗法口服给药时，JNJ-17029259可延缓裸鼠体内多种人肿瘤异种移植物的生长。组织学检查显示，治疗后肿瘤有血管减少的迹象。此外，当联合治疗口服给药时，JNJ-17029259可增强传统化疗药物阿霉素和紫杉醇在异种移植模型中的作用。一种可口服的血管生成抑制剂，可与标准化疗药物联合使用以增强其活性，可能对阻止癌症进展和预防转移具有治疗益处。
