Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy
Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy
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DOI：
10.1038/sj.mt.6300096
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发表时间：
2007-04-01
影响因子：
12.4
通讯作者：
Kumon, Hiromi
中科院分区：
文献类型：
--
作者：
Nasu, Yasutomo;Saika, Takashi;Kumon, Hiromi
我们开展了原位单纯疱疹病毒胸苷激酶（HSV-tk）联合更昔洛韦（GCV）基因治疗的I期研究，该研究被日本政府批准为首个前列腺癌基因治疗试验。主要入选标准为激素治疗后前列腺癌局部复发及无转移。将Adv.HSV-tk按递增剂量从109个感染单位直接注射到前列腺，然后静脉注射GCV，持续14天。8名患者接受了9个疗程的基因治疗。在血液/尿液中检测到载体DNA只是短暂的，在任何患者中未观察到明显的不良事件。在临床反应方面，血清前列腺特异性抗原（PSA）中位倍增时间从2.9个月显著延长至6.2个月（P=0.041）。在5例患者（6次注射）中，观察到PSA值明显下降。1例患者多次注射后出现反复临床反应。治疗后血清细胞因子分析无明显变化。荧光活化细胞分选分析也显示，除了治疗后CD8(+)/HLA-DR+呈增加趋势外，对外周血样本的表型分布没有影响。本研究证实了HSV-tk基因治疗激素难治性前列腺癌的安全性和替代标志物水平的临床反应可能性。
We conducted a Phase I study of in situ herpes simplex virus thymidine kinase (HSV-tk) plus ganciclovir (GCV) gene therapy, which was approved by the Japanese government as the first prostate cancer gene therapy trial. Major inclusion criteria were local recurrence of prostate cancer after hormonal therapy and no metastasis. Adv.HSV-tk was injected directly into the prostate in escalating doses from 109 to 101 infection units, followed by intravenous administration of GCV for 14 days. Eight patients received nine courses of this gene therapy. The detection of vector DNA in blood/urine was only transient and no remarkable adverse events were observed in any patient. With regard to clinical response, significant prolongation of the median serum prostate-specific antigen (PSA) doubling time from 2.9 to 6.2 months (P=0.041) was detected. In five patients (six injections), a clear decrease of PSA values was observed. One patient showed repeated clinical response after repeated injections. Serum cytokine analysis showed no notable changes after treatment. Fluorescence-activated cell sorting analysis also showed no influence on phenotypic distribution in peripheral blood samples, except for an increasing trend of CD8(+)/HLA-DR+ after therapy. This study confirmed the safety profile and possibility of clinical response at the surrogate marker level in a clinical trial of HSV-tk gene therapy for hormone-refractory prostate cancer.