Efficacy of Combination Therapy of Ionizing Radiation and Gene Therapy in Prostate Cancer in vitro

电离辐射与基因治疗联合治疗前列腺癌的体外疗效

• 批准号: 12670871
• 负责人: SOEJIMA Toshinori
• 金额: $ 1.73万
• 依托单位: Kobe University Graduate School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670871/
• 关键词: radiation therapy; gene therapy; p53; adenovirus vector; apoptosis; cell cycle; prostate cancer; 粒子線治療; DNA; DNA修復; Rad51; 併用療法; アデノウイルス; 併用治療; 放射線

Several studies have demonstrated that the function of the p53 gene is one of the major determinants of intrinsic cellular sensitivity to the cytotoxic effects of ionizing radiation (IR). Moreover, a strategy to combine adenovirus-mediated wild-type p53 gene transfer with DNA-damaging treatments, such as IR and chemotherapeutic agents, has also been studied in glioblastoma, lung, colorectal, ovarian, and head-and-neck cancers, and additional cytotoxicity or tumor-suppressing activity has been consistently observed. In prostate cancer cells, the significant cytotoxicity has been previously reported with the induction of recombinant wild-type p53 adenovirus (Ad5CMV-p53). In this study, the interactions between IR and Ad5CMV-p53 gene therapy in two androgen-independent prostate cancer cell lines (DU145 and PC-3) were evaluated. We demonstrated that this combination therapy resulted in remarkable synergistic effects and also assessed its molecular mechanisms. The cell growth inhibition in … More DU145 (p53-mutated) cells by IR was strongly enhanced by additional Ad5CMV-p53 infection in a viral dose-dependent manner. In DU145 cells, IR alone induced minimal p53 mRNA expression. However, IR combined with Ad5CMV-p53 infection stimulated significant increase in p53 mRNA expression supplemented with Bax and p21 mRNA expressions. In PC-3 (p53-null), IR induced Bax and p21 mRNA expression, while the combination effects were observed in p53, Bax, and p21 mRNA expression. Apoptotic cell deaths were rarely observed after IR alone (DU145: 3%, PC-3: 5%). However, after combination therapy, the proportion of apoptotic cells greatly increased (sevenfold in DU145 cells, and twice in PC-3 cells). G1 cell cycle arrest was observed after Ad5CMV-p53 infection and the combination in both cell lines. In conclusion, Ad5CMV-p53 infection enhances the effect of radiation therapy by efficient induction of apoptosis and cell cycle arrest. This combination therapy could be one of the optimal treatment strategies for radioresistant prostate cancer. Less

一些研究表明，P53基因的功能是决定细胞对电离辐射(IR)细胞毒性效应的内在敏感性的主要决定因素之一。此外，将腺病毒介导的野生型p53基因转移与DNA损伤治疗(如IR和化疗药物)相结合的策略也已在胶质母细胞瘤、肺癌、结直肠癌、卵巢癌和头颈癌中进行研究，并一直观察到额外的细胞毒性或肿瘤抑制活性。在前列腺癌细胞中，先前报道了重组野生型P53腺病毒(Ad5CMV-P53)诱导的显著细胞毒作用。本研究探讨了IR与Ad5CMV-P53基因治疗在雄激素非依赖性前列腺癌DU145和PC-3细胞中的相互作用。我们证明了这种联合疗法产生了显著的协同效应，并对其分子机制进行了评估。…中的细胞生长抑制额外的Ad5CMV-P53感染以病毒剂量依赖的方式增强了IR诱导的更多DU145(P53突变)细胞。在DU145细胞中，IR单独诱导最低水平的P53基因表达。然而，IR联合Ad5CMV-P53感染刺激P53基因表达显著增加，并补充Bax和p21基因的表达。在PC-3(p53缺失)中，IR诱导Bax和p21mRNA的表达，而联合作用对p53、Bax和p21mRNA的表达有影响。单独IR后很少观察到凋亡细胞死亡(DU145：3%，PC-3：5%)。然而，联合治疗后，凋亡细胞的比例大大增加(DU145细胞是DU145细胞的七倍，PC-3细胞是DU145细胞的两倍)。Ad5CMV-P53和Ad5CMV-P53联合感染后，两株细胞均出现G1期细胞周期阻滞。结论：Ad5CMV-P53感染通过有效地诱导细胞凋亡和细胞周期停滞来增强放射治疗的效果。这种联合疗法可能是放射抵抗前列腺癌的最佳治疗策略之一。较少

项目成果

Shirakawa T.: "p53 adenoviral vector (Ad-CMV-p53) induced prostatic growth inhibition of primary cultures of human prostate and an experimental rat model"J Gene Med. 2(6). 426-432 (2000)

Shirakawa T.：“p53 腺病毒载体 (Ad-CMV-p53) 诱导人前列腺原代培养物和实验大鼠模型的前列腺生长抑制”J Gene Med。

Shirakawa T: "p53 adenoviral vector (Ad-CMV-p53) induced prostatic growth inhibition of primary cultures of human prostate and an experimental rat model"J Gene Med. 2(6). 426-432 (2000)

Shirakawa T：“p53 腺病毒载体 (Ad-CMV-p53) 诱导人前列腺原代培养物和实验大鼠模型的前列腺生长抑制”J Gene Med。

Sasaki R.: "Additional gene therapy with Ad5CMV-p53 enhanced the efficacy of radiotherapy in human prostate cancer cells"Int J Radiat Oncol Biol Phys. 51(5). 1336-1345 (2001)

Sasaki R.：“Ad5CMV-p53 的额外基因治疗增强了人类前列腺癌细胞放射治疗的功效”Int J Radiat Oncol Biol Phys。

Shirakawa T.: "Drug-resistant human bladder-cancer cells are more sensitive to adenovirus-mediated wild-type p53 gene therapy compared to drug-sensitive cells"Int J Cancer. 94(2). 282-289 (2001)

Shirakawa T.：“与药物敏感细胞相比，耐药人类膀胱癌细胞对腺病毒介导的野生型 p53 基因治疗更敏感”Int J Cancer。

Gotoh A: "Gene therapy for prostate cancer"Hinyokika Kiyo. 48(11). 729-732 (2002)

Gotoh A：“前列腺癌的基因治疗”Hinyokika Kiyo。