Targeting suicide gene therapy for prostate cancer utilizing HVJ-liposome

利用 HVJ 脂质体针对前列腺癌进行自杀基因治疗

• 批准号: 12671556
• 负责人: HORIGUCHI Yutaka
• 金额: $ 2.3万
• 依托单位: Keio University
• 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 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671556/
• 关键词: enhancer; gene therapy; liposome; promotor; prostate cancer; suicide gene therapy; targeting; tissue-specific; ターゲティング; 特異的プロモーター

For advanced stage of prostate cancers, androgen ablation is the standard choice of treatment and initially it is effective for the majority of patients. However, once cancer becomes relapsed and refractory to androgen ablation therapy, there is no clear consensus of treatments that overcome this disease. Thus, various gene therapies against prostate cancer, especially in a tissue-specific manner, are currently being widely investigated.Prostate-specific membrane antigen (PSMA) is a transmembrane protein predominantly expressed on human neoplastic prostate epithelial cells. For the development of targeting gene therapy, we are investigating a tissue-specific promoter of PSMA gene. A 1244bp DNA fragment consisted of 5'-flanking region of PSMA gene was cloned into a luciferase reporter plasmid. In PSMA producing LNCaP human prostate cancer cell line, putative PSMA promoter activity was approximately 40% of that of the SV40 promoter/enhancer and it was inversely increased with androgen depletion. While, in other non-PSMA producing prostate and non-prostate cancer cell lines, the promoter activity was not higher than 11% of its control and independent to the androgen concentration. Further evaluation with its deletion constructs revealed possible negative regulatory elements in the PSMA promoter. These unique features of the PSMA promoter in contrast to the prostate-specific antigen promoter will be potentially useful for targeting gene therapy against PSMA producing prostate cancers.

对于前列腺癌的晚期阶段，雄激素消融是治疗的标准选择，最初对大多数患者有效。但是，一旦癌症复发并难治于雄激素消融疗法，就没有明确的治疗方法来克服这种疾病。因此，目前正在广泛研究针对前列腺癌的各种基因疗法，尤其是在组织特异性的情况下。前验特异性的膜抗原（PSMA）是一种跨膜蛋白，主要在人类肿瘤前列腺上皮细胞上表达。为了开发靶向基因治疗，我们正在研究PSMA基因的组织特异性启动子。一个1244bp的DNA片段由PSMA基因的5'Fantanking区组成，将其克隆到荧光素酶报告基因质粒中。在产生LNCAP人前列腺癌细胞系的PSMA中，推定的PSMA启动子活性约为SV40启动子/增强子的40％，并且随着雄激素的耗竭而成反比。而在其他产生前列腺和非肢体癌细胞系的非PSMA中，启动子活性不超过其对照的11％，并且独立于雄激素浓度。进一步的评估及其缺失构建体显示PSMA启动子中可能的负调节元素。与前列腺特异性抗原启动子相比，PSMA启动子的这些独特特征将有可能对靶向基因疗法靶向PSMA产生前列腺癌。