Targeting suicide gene therapy for prostate cancer utilizing HVJ-liposome

对于晚期前列腺癌，雄激素消融术是标准的治疗选择，最初对大多数患者有效。然而，一旦癌症复发并对雄激素消融治疗无效，就没有明确的共识来克服这种疾病。因此，目前针对前列腺癌的各种基因治疗方法，特别是针对组织特异性的基因治疗方法，正在被广泛研究。前列腺特异性膜抗原(PSMA)是一种主要表达于人前列腺癌上皮细胞的跨膜蛋白。为了发展靶向基因治疗，我们正在研究一种组织特异性的PSMA基因启动子。将含有PSMA基因5‘侧翼区的1244bpDNA片段克隆到荧光素酶报告载体中。在PSMA产生LNCaP的人前列腺癌细胞系中，PSMA启动子的活性约为SV40启动子/增强子活性的40%，并且随着雄激素的耗竭而相反增加。而在其他非PSMA产生的前列腺癌和非前列腺癌细胞系中，启动子活性不高于其对照的11%，且与雄激素浓度无关。通过对其缺失结构的进一步评估，揭示了PSMA启动子中可能存在的负调控元件。与前列腺特异性抗原启动子相比，PSMA启动子的这些独特功能将潜在地用于针对产生PSMA的前列腺癌的靶向基因治疗。

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.