Induction of apoptosis against cytokine-producing urological cancer

本研究旨在探讨针对细胞因子产生细胞的癌症基因治疗。首先，我们成功地建立了以肾(KU-19-20)和膀胱(KU-19-19)为靶细胞的人泌尿系癌细胞产生细胞因子的模型。这些细胞可分泌多种细胞因子，如粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、白介素6(IL-6)和IL-8。然后，我们研究了核因子-kappaB(NF-κ-B)是否能调节细胞生长和细胞因子产生细胞的凋亡。用腺病毒载体将IκB稳定型c DNA(已知为核因子κB抑制剂)导入细胞，可显著抑制细胞内多种细胞因子的产生。值得注意的是，通过基因治疗也观察到了显著的诱导细胞凋亡。这些结果表明，在产生细胞因子的癌细胞中，核因子κB的激活维持细胞活力并调节细胞因子的产生，因此，这些体外实验支持了临床前体内研究的理论基础，以证明对已建立的肿瘤的生长抑制。

This study was designed to investigate cancer gene therapy against cytokine producing cells. Firstable, we succeeded establishment of cytokine producing human urological cancer cells including kidney (KU-19-20) and bladder (KU-19-19) as a target model. These cells have been shown to secrete a variety of cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interleiukin-6 (IL-6) and IL-8. Then we investigated whether the cell growth and apoptosis of cytokine-producing cells can be regulated by nuclear factor kappa B (NFκB). When IκB stable form cDNA (which is known to be the NFκB inhibitor) was transfected into the cells with adenovirus vector, the production of several cytokines was significantly suppressed in these cells by the gene delivery. Notably, the significant induction of apoptosis was also observed by the gene therapy. These results suggest that NFκB activation maintains the cell viability as well as regulates cytokine production in cytokine-producing cancer cells and therefore these in vitro experiments support a rationale for preclinical in vivo studies to demonstrate growth inhibition in established tumors.