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。最近，基因治疗作为一种新的治疗方式被引入到局部和转移疾病的治疗中。我们已经确定了前列腺癌细胞和转导前列腺特异性抗原(PSA)启动子的非前列腺癌细胞的雄激素反应性和PSA分泌状态。雄激素非依赖性(AI)人前列腺癌仍然是一种致命的表型，目前还没有有效的治疗方法。AI前列腺癌在原发灶和转移灶产生和分泌大量PSA。本研究的目的是探索使用PSA启动子作为前列腺细胞特异性表达有毒基因胸苷激酶(TK)的手段，以产生AI PSA的人前列腺癌细胞系。我们比较了PSA启动子在体内和体外对几种人类细胞株的治疗效果。构建了PSA启动子控制下携带人单纯疱疹病毒胸苷激酶(TK)基因的腺病毒载体(Ad-PSA-TK)，用于靶向产生PSA的AI前列腺癌细胞。PSA启动子是在产生PSA的前列腺癌细胞中高效、特异表达治疗基因的有力候选者。在阿昔洛韦的作用下，Ad-PSA-TK在体内外有效地杀伤了产生AI PSA的人前列腺癌细胞。我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。我们的策略可以与现有的治疗方法结合使用，以实现更有效的肿瘤细胞杀伤，同时大大降低毒性。

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.