Application for PTEN Gene Therapy in Prostate Cancer

PTEN基因治疗在前列腺癌中的应用

• 批准号: 15591709
• 负责人: TANAKA Motoyoshi
• 金额: $ 2.24万
• 依托单位: Nara Medical University 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591709/
• 关键词: Prostate cancer; PTEN tumor suppressor gene; gene therapy; PTEN

We have demonstrated that an adenoviral gene therapy of PTEN can effectively treat bladder and prostate cancers, and can be effectively treated tumors which exhibit drug or radiation resistance associated with expression of phosphorylated Akt in combination with chemotherapy or radiotherapy. PTEN is well known as a tumor suppressor gene and has a phosphatase activity in the phosphatidylinositol 3'-kinase mediated signal transduction pathway and inhibits the activation of Akt, a serine-threonine kinase involved in proliferative and anti-apoptotic pathways. These days, using virus vector for cancer gene therapy is controversial, and non-viral gene transfer is a future promising procedure but several problems need to be cleared, such as transduction efficacy. We have developed non-viral compound conjugated with cationized gelatin microsphere and plasmid DNA, which is a new type of gene transfer drug and designed to release plasmid DNA and last the gene expression continuously for a long p … More eriod in vivo. In this study, we originally generated the GelaTen, which is a conjugate with cationized gelatin microsphere (2 mg) and PTEN expression vector (100 μg), and examined the efficacy of GelaTen as a combination therapy with radiation in prostate cancer. Single direct injection of GelaTen into established subcutaneous bcl-2-overexpressing PC3 prostate cancer tumors (PTEN deleted, up-regulation of phosphorylated Akt and Bcl-2) in nude mice, which reached approximately 5-7mm in diameter, resulted in significantly decreased growth compared to the conjugate with ss-gal plasmid (control) or PBS treated tumors. Immunohistochemical analysis showed that tumors inducted with GelaTen expressed PTEN and exhibited decreased amounts of phosphorylated Akt, whereas tumors treated with CTL or PBS were negative for PTEN and diffusely positive for phosphorylated Akt. Since PTEN downregulates phosphorylated Akt and Bcl-2 and increases sensitivity to radiation, we explored combination therapy with GelaTen and radiation in vivo. Combination therapy with GelaTen and 5 Gy irradiation (5 days after GelaTen injection) improved the in vivo efficacy of tumor growth compared to the GelaTen monotherapy alone in these tumors. These data demonstrate that PTEN gene therapy with gene drug GelaTen can effectively treat prostate cancers that have genomic alterations in PTEN. Furthermore, tumors that exhibit radiation resistance associated with expression of phosphorylated Akt and Bcl-2 can be effectively treated with GelaTen and radiotherapy. Less

我们已经证明，PTEN的腺病毒基因治疗可以有效地治疗膀胱癌和前列腺癌，并且可以有效地治疗与磷酸化Akt表达相关联的耐药或放射耐药的肿瘤，并结合化疗或放射治疗。PTEN是一个众所周知的肿瘤抑制基因，在磷脂酰肌醇3‘-激酶介导的信号转导通路中具有磷酸酶活性，并抑制Akt的激活，Akt是一种参与增殖和抗凋亡通路的丝氨酸-苏氨酸激酶。目前，使用病毒载体进行肿瘤基因治疗存在争议，非病毒基因转移是一种很有前途的方法，但有几个问题需要解决，如转导效果。我们研制了阳离子明胶微球与质粒dna偶联的非病毒化合物，这是一种新型的基因转移药物，旨在释放质粒dna并使基因持续表达较长时间(p…)。活体内的时间更长。在本研究中，我们首次制备了与阳离子明胶微球(2 Mg)和PTEN表达载体(100μg)的偶联物GelaTen，并检测了GelaTen作为放射联合治疗前列腺癌的疗效。单次直接注射GelaTen到裸鼠皮下高表达bcl2的PC3前列腺癌(PTEN缺失，磷酸化Akt和Bcl2上调)肿瘤中，肿瘤直径约5-7 mm，与单链半乳糖(对照)或PBS处理的肿瘤相比，肿瘤生长明显减慢。免疫组织化学分析显示，GelaTen诱导的肿瘤表达PTEN，磷酸化Akt表达减少，而CTL或PBS治疗的肿瘤PTEN阴性，磷酸化Akt广泛阳性。由于PTEN下调Akt和Bcl2的磷酸化水平，增加对辐射的敏感性，我们探索了GelaTen和辐射的体内联合治疗。在这些肿瘤中，与GelaTen单独治疗相比，GelaTen和5Gy射线联合治疗(注射GelaTen后5天)改善了肿瘤生长的体内疗效。这些数据表明，PTEN基因治疗联合基因药物GelaTen可以有效地治疗PTEN基因突变的前列腺癌。此外，GelaTen和放射治疗可以有效地治疗与磷酸化Akt和Bcl-2表达相关的辐射抵抗的肿瘤。较少