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Targeting gene therapy for prostate cancer using prostate specific antigen (PSA)

使用前列腺特异性抗原 (PSA) 进行前列腺癌靶向基因治疗

基本信息

批准号：
09470352
负责人：
MURAI Masaru
金额：
$ 7.49万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-09470352/
关键词：
prostate cancer PSA gere therapy プロモーター 5-fluorocytosine Cytosine deminase

项目摘要

As a new treatment of prostate cancer, we are investigating a gene therapy model that utilizes a suicide gene cytosine deaminase (CD) that metabolizes non-toxic 5-fluorocytosine (5-FC) into toxic 5-fluorouracil (5-FU) in a LNCaP human prostate cancer model. The vector pC/CD was used to transfect LNCaP cells. 5 -FC showed a significantly lower ID50 value against the clones LN/CD than the control cells transfected with an empty vector, which was sensitive to 5-FU.Tumors made with LN/CD inoculation in nude mice were shown to regress after i.p.administration of 5-FC.The expression of the CD gene was effective in therapy of the LNCaP prostate cancer model both in vitro and in vivo. We used regulatory elements from the PSMA gene to develop a construct that could be used to control expression of a CD gene in a gene therapy approach against this disease. We recently cloned the promoter of the PSMA gene, which can drive prostate-specific expression of a luciferase reporter gene.NF κ B inhibitors, pyrrolidine dithiocarbamate (PDTC) and NF κ B decoy, continuously inhibited TNF-α-induced NF κ B activation. Prostate cancer cells treated with TNF-α (20 ng/ml) plus NF κ B inhibitors showed significant growth inhibition. The combination of TNF-α and NF κ B inhibitors was suggested to be an effective therapy for prostate cancer.We evaluate the antitumoral effect of a conditionally-replicating herpes simplex virus 1 (HSV-1) vector, G207, against prostate cancer in vitro and in vivo. DU145 and PC3 were efficiently destroyed by G207 within 7 days. The viral yields of G207 increased time-dependently. In vivo, the intraneoplastic inoculation of G207 induced a significant inhibition of the tumor growth. In a pathological study, a large number of lacZ positive cells were diffusely present in the G207-treated tumors. G207 thus may be considered a useful agent for the treatment of prostate cancer.

作为前列腺癌的一种新治疗方法，我们正在研究一种基因治疗模型，该模型利用自杀基因胞嘧啶脱氨酶（CD），在LNCaP人前列腺癌模型中将无毒的5-氟胞嘧啶（5-FC）代谢为有毒的5-氟尿嘧啶（5-FU）。用pC/CD载体转染LNCaP细胞。5 -FC对LN/CD细胞株的ID_（50）值明显低于空载体转染的对照细胞，对5-FU敏感，腹腔注射5-FC后，LN/CD裸鼠移植瘤消退，CD基因表达对LNCaP前列腺癌模型的体内外治疗均有效。我们使用来自PSMA基因的调控元件开发了一种构建体，该构建体可用于在针对该疾病的基因治疗方法中控制CD基因的表达。我们最近克隆了PSMA基因的启动子，它可以驱动荧光素酶报告基因的前列腺特异性表达。NF κ B抑制剂，吡咯烷二硫代氨基甲酸酯（PDTC）和NF κ B诱饵，持续抑制TNF-α诱导的NF κ B活化。用TNF-α（20 ng/ml）加NF κ B抑制剂处理的前列腺癌细胞显示出显著的生长抑制。TNF-α和NF κ B抑制剂的联合应用是治疗前列腺癌的有效方法，我们研究了条件复制型单纯疱疹病毒1型（HSV-1）载体G207在体内外抗前列腺癌的作用。G207对DU 145和PC 3在7天内有很好的杀灭效果。G207的病毒产量呈时间依赖性增加。在体内，肿瘤内接种G207诱导了显著的肿瘤生长抑制。在病理学研究中，大量lacZ阳性细胞弥漫存在于G207处理的肿瘤中。因此，G207可以被认为是用于治疗前列腺癌的有用药剂。