Basic research of gene targeting and molecular targeting therapy for relapse of prostate cancer

由于尚不清楚晚期前列腺癌在激素治疗期间复发的原因，我们从雄激素敏感细胞系LNCaP中建立了雄激素非依赖型前列腺癌LNCaP- sf和LN-REC4细胞。我们对这些细胞系进行了表征，以研究哪些机制参与了进展。LNCaP-SF细胞在没有雄激素的情况下增殖受到刺激，在有雄激素的情况下增殖受到抑制。提示LN-REC4诱导血管生成。现在我们正在研究受雄激素不同调控的基因。利用LNCaP-SF细胞成功建立前列腺癌成骨转移模型。破骨细胞在前列腺癌细胞成骨转移中发挥了重要作用，我们证实了第三代双膦酸盐能够抑制前列腺癌成骨转移和溶骨转移。通过抑制破骨细胞。此外，双膦酸盐不仅通过破骨细胞发挥间接作用，还可以通过抑制趋化因子受体CXCR-4的表达直接诱导癌细胞凋亡和抑制侵袭。提示第三代双膦酸盐具有预防前列腺癌骨转移的药物作用。为了开发肿瘤基因Her-2的分子靶标药物，我们假设Her-2在复发性前列腺癌中表达增强，我们还使用了Her-2特异性酪氨酸激酶抑制剂，并在体外和体内证实了其抗肿瘤作用。

Since it is not clear why advanced prostate cancer relapses during hormone therapy, we established androgen-independent prostate cancer, LNCaP-SF and LN-REC4 cells from androgen-sensitive cell line, LNCaP. We characterized these cell lines in order to investigate what kinds of mechanisms are involved in progression. LNCaP-SF cells proliferation was stimulated in the absence of androgen and repressed in the presence of androgen. It was suggested that LN-REC4 induced angiogenesis. Now we are investigating the genes which are differentially regulated by androgen.We also succeeded in establishment of osteoblastic metastatic model of prostate cancer using LNCaP-SF cells. Osteoclast showed important role in osteoblastic metastasis of prostate cancer cells, and we certified that the 3rd generation of bisphosphonates could inhibit osteoblastic bone metastasis as well as osteolytic bone metastasis of prostatic cancer. through inhibition of osteoclast. Furthermore, bisphosphonates not only showed indirect action through osteoclast but also directly induced apoptosis of cancer cells and inhibited invasion through repression of chemokine receptor, CXCR-4 expression. These results indicate that the 3rd generation of bisphosphonates has potency of bone metastasis preventive medicine for prostate cancer.For development of molecular target drug for oncogene Her-2 assumed that the expression is enhanced in recrudescence prostatic cancer, we also used Her-2 specific-tyrosine kinase inhibitor and confirmed the antitumor effect in vitro and in vivo.