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Basic Research into Clinical Application of Gene Therapy for Prostate Cancer

前列腺癌基因治疗临床应用基础研究

基本信息

批准号：
09671628
负责人：
GOTOH Akinobu
金额：
$ 1.66万
依托单位：
Kobe 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：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671628/
关键词：
Prostate cancer Prostate Specific Antigen(PSA)tissue specific promoter Thymidine Kinase(TK)Adenovirus Gene Therapy Clinical Application PSA ベクターホルモン不応 P53 癌抑制遺伝子

项目摘要

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.

过去前列腺癌的治疗涉及手术、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，用于治疗局部和转移性疾病。我们已经定义了前列腺癌细胞以及用 PSA 启动子报告基因构建体转导的非前列腺细胞的雄激素反应性和前列腺特异性抗原 (PSA) 分泌状态。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 前列腺癌在原发部位和转移部位产生并分泌大量 PSA。本研究的目的是探索使用 PSA 启动子作为毒性基因胸苷激酶 (TK) 的前列腺细胞在体外和体内对产生 AI PSA 的人前列腺癌细胞系进行特异性表达的手段。我们在体外和体内比较了 PSA 启动子在几种人类细胞系中的治疗效果。产生了一种携带受 PSA 启动子控制的人单纯疱疹胸苷激酶 (TK) 基因 (Ad-PSA-TK) 的腺病毒载体，以靶向产生 PSA 的 AI 前列腺癌细胞。 PSA 启动子是产生 PSA 的前列腺癌细胞中治疗基因高特异性表达的有力候选者。给予阿昔洛韦后，Ad-PSA-TK在体外和体内有效杀死产生AI PSA的人前列腺癌细胞。我讨论了组织特异性启动子系统对于前列腺癌基因治疗的重要性，并总结了基因治疗在AI前列腺癌临床应用的潜力。我们的策略可能可以与当前的治疗方式结合使用，以实现更有效的肿瘤治疗细胞杀伤，毒性大大降低。