Basic Research into Clinical Application of Gene Therapy for Prostate Cancer

过去前列腺癌的治疗包括手术、放射治疗、激素和/或化疗。近年来，基因治疗作为一种新的治疗方式被引入到局部和转移性疾病的治疗中。我们定义了前列腺癌细胞和非前列腺细胞的前列腺特异性抗原（PSA）分泌的雄激素反应性和状态，这些细胞被PSA启动子报告构建物转导。雄激素非依赖性（AI）人类前列腺癌仍然是一种致命的表型，目前尚无有效的治疗方法。AI前列腺癌在原发和转移部位均产生和分泌大量PSA。本研究的目的是探索在体外和体内使用PSA启动子作为毒性基因胸苷激酶（TK）对产生AI PSA的人前列腺癌细胞系的前列腺细胞特异性表达的平均值。我们在体外和体内比较了PSA启动子对几种人类细胞系的治疗效果。在PSA启动子（Ad-PSA-TK）的控制下，制备了一种携带人类单纯疱疹胸苷激酶（TK）基因的腺病毒载体，用于靶向产生PSA的AI前列腺癌细胞。PSA启动子是PSA产生前列腺癌细胞中高特异性表达治疗基因的有力候选。Ad-PSA-TK在体外和体内均能有效杀伤产生AI psa的人前列腺癌细胞。讨论了组织特异性启动子系统在前列腺癌基因治疗中的重要性，并总结了基因治疗在AI前列腺癌临床应用的潜力。我们的策略有可能与目前的治疗方式结合使用，以实现更有效的肿瘤细胞杀伤和更低的毒性。

Treatment of prostate cancer in the past has involved surgery, radiation therapy, hormonal and/or chemotherapy. Recently, gene therapy was introduced as a new therapeutic modality for the treatment of both localized and metastatic diseases. We have defined the androgen responsiveness and status of Prostate Specific Antigen(PSA) secretion of prostate cancer cells as well as non prostatic cells transduced with PSA promoter reporter constructs. Androgen-independent (AI) human prostate cancer remains a lethal phenotype for which there is no effective therapy. AI prostate cancer produces and secretes large amounts of PSA at both primary and metastatic sites. The aim of this investigation is to explore the use of the PSA promoter as a mean of prostate cell specific expression of a toxic gene thymidine kinase(TK) to an AI PSA-producing human prostate cancer cell line in vitro and in vivo. We compared the therapeutic efficacy of the PSA promoter in several human cell lines in vitro and in vivo. An adenovirus vector carrying human herpes simplex thymidine kinase(TK) gene under control of the PSA promoter (Ad-PSA-TK) was generated to target PSA-producing AI prostate cancer cells. The PSA promoter is a strong candidate for high, specific expression of therapeutic genes in PSA producing prostate cancer cells. Upon the administration of acyclovir, Ad-PSA-TK efficiently killed the AI PSA-producing human prostate cancer cells in vitro and in vivo.I discuss the importance of tissue specific promoter system for using gene therapy of prostate cancer, and summarize the potential for clinical application of gene therapy to AI prostate cancer.This our strategy potentially can be used in combination with current therapeutic modalities to achieve more effective tumor cell-kill with much reduced toxicity.