Treatment efficiency of a suicide gene therapy using prostate-specific membrane antigen promoter/enhancer in a castrated mouse model of prostate cancer
Treatment efficiency of a suicide gene therapy using prostate-specific membrane antigen promoter/enhancer in a castrated mouse model of prostate cancer
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DOI：
10.1111/j.1349-7006.2004.tb03217.x
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发表时间：
2004-04-01
期刊：
影响因子：
5.7
通讯作者：
Hayakawa, M
中科院分区：
文献类型：
--
作者：
Ikegami, S;Tadakuma, T;Hayakawa, M
自杀基因疗法有可能治疗雄激素缺乏条件下的前列腺癌。我们发现前列腺特异性膜抗原(PEPM)启动子/增强子(PEPM)与Cre-IoxP系统相结合是一种在前列腺癌细胞中表达自杀基因即疱疹病毒胸苷激酶(TK)的好方法。我们在体内的去势模型中检查了该系统，并与前列腺特异性抗原启动子/增强子系统(PP)进行了比较。在去势小鼠中，PEPM+Cre-IoxP系统的肿瘤荧光素酶活性是对照GL3质粒的50倍左右。在未去势的小鼠身上也观察到了类似的增加。相反，在去势小鼠的肿瘤中，与未去势的对照小鼠的肿瘤相比，质粒PIP的荧光素酶活性显著降低。在治疗效果方面，PEPM-CRE+CMV-IoxP-TK对去势小鼠的肿瘤生长有较强的抑制作用，与未去势小鼠一样。而PP-TK在去势小鼠体内未表现出明显的生长抑制作用。这些结果表明，在体内雄激素消融条件下，PEPM和Cre-IoxP系统的联合应用可能会有良好的治疗效果，因此我们的系统可能适用于既往接受雄激素去势治疗的患者。
Suicide gene therapy has potential for the treatment of prostate cancer under conditions of androgen deprivation. We show here that the combination of promoter/ enhancer of prostate-specific membrane antigen (PEPM) and the Cre-IoxP system is a good method to express a suicide gene, namely herpes virus thymidine kinase (TK), in prostate cancer cells. We have examined this system in a castration model in vivo, in comparison with a prostate-specific antigen promoter/enhancer system (PP). In the castrated mice, the tumor luciferase activity with the combination of the PEPM plus the Cre-IoxP system was about 50 times greater than that with the control GL3 plasmid. A similar increase was observed in non-castrated mice. In contrast, the luciferase activity of the plasmid PIP was decreased significantly in tumors from castrated mice as compared with tumors from non-castrated control mice. Regarding the therapeutic effect, the combination plasmid PEPM-Cre plus CMV-IoxP-TK exhibited a strong inhibitory effect on tumor growth in the castrated mice, as in the non-castrated mice. In contrast, PP-TK plasmid did not show any significant growth inhibition in the castrated mice. These findings indicate that the combination of PEPM and Cre-IoxP system may have a good treatment effect under androgen ablation conditions in vivo, and our system may therefore be applicable to patients who have previously received androgen deprivation therapy.