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，对激素难治性前列腺癌具有生长抑制作用。为了研究辐射和一种抗癌药物与FGFR2在激素难治性人前列腺癌细胞中的协同作用，我们转染了一种激素难治性人前列腺癌细胞系PC3。采用流式细胞术和Annexin亲和实验分别评价放疗和多西他赛对细胞周期和凋亡的影响。FGFR2在PC3细胞中的表达导致体外生长抑制和体内肿瘤形成减少，同时增加细胞分化和凋亡。4 ~ 8gy的辐射进一步降低了转染PC3细胞的菌落数量。膜联蛋白亲和实验显示，8gy辐射可引起转染PC3细胞明显凋亡。8 Gy辐照24 h后，转染PC3细胞的G2/M期比例明显高于模拟细胞。多西紫杉醇对转染的PC3细胞也有类似的作用。这些结果表明，放射和多西他赛增强了激素难治性人前列腺癌细胞中FGFR2的生长抑制活性。FGFR2联合放疗或多西他赛可能为激素难治性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.