Development of a novel therapy for hormone-refractory prostate cancer

研究结果成纤维细胞生长因子受体2(FGFR2)是一种受体型酪氨酸激酶，对激素非依赖性前列腺癌具有生长抑制作用。为了研究辐射和抗癌剂与FGFR2在激素非依赖性人前列腺癌细胞中的协同作用，将FGFR2基因导入激素非依赖性人前列腺癌细胞系PC3。分别用流式细胞仪和膜联蛋白亲和分析检测放射或多西紫杉醇对PC3细胞周期和细胞凋亡的影响。FGFR2在PC3细胞中的表达导致体外生长抑制和体内肿瘤形成，同时增加细胞分化和凋亡。4~8Gy射线照射后，PC3细胞的集落数进一步减少。Annexin亲和分析表明，8Gy射线照射后PC3细胞发生明显的细胞凋亡。8Gy射线照射后24小时，PC3细胞的G2/M期比例明显高于Mock细胞。多西紫杉醇对PC3细胞也有类似的作用。这些结果表明，放射和多西紫杉醇增强了FGFR2在激素耐药的人前列腺癌细胞中的生长抑制活性。FGFR2联合放疗或多西紫杉醇可能为激素耐药前列腺癌的基因治疗提供新的途径。

RESEARCH RESULTS Fibroblast growth factor receptor 2 (FGFR2) is a receptor-type tyrosine kinase that has a growth inhibitory effect on hormone-refractory prostate cancer. To investigate the synergistic effects of radiation and an anticancer agent with FGFR2 in hormone-refractory human prostate cancer cells, a hormone-refractory human prostate cancer cell line, PC3, was transfected with FGFR2. The effects of radiation or docetaxel on cell cycle and apoptosis were evaluated by flowcytometry and Annexin affinity assay, respectively.Expression of FGFR2 in PC3 cells resulted in growth suppression in vitro and reduced tumor formation in vivo concurrent with increased cellular differentiation and apoptosis. Four to 8 Gy of radiation further decreased the number of colonies in transfected PC3 cells. Annexin affinity assay revealed that 8 Gy of radiation caused significant apoptosis for transfected PC3 cells. Also, at 24 hours after 8 Gy of radiation, proportion of G2/M phase was significantly higher in the transfected PC3 cells than in Mock cell. Docetaxel showed similar effects on the transfected PC3 cells.These results indicate that radiation and docetaxel enhance the growth-suppressive activity of FGFR2 in hormone-refractory human prostate cancer cells. Combination of FGFR2 with radiation or docetaxel may provide a new avenue for gene therapy of hormone-refractory prostate cancer.