Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer.
Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer.
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发表时间：
2002-09
期刊：
影响因子：
11.2
通讯作者：
S. Freytag;M. Khil;H. Stricker;J. Peabody;M. Menon;M. Deperalta-Venturina;Daniel Nafziger;J. Pegg;D. Paielli;S. Brown;K. Barton;Mei Lu;E. Aguilar‐Cordova;J. H. Kim
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作者：
S. Freytag;M. Khil;H. Stricker;J. Peabody;M. Menon;M. Deperalta-Venturina;Daniel Nafziger;J. Pegg;D. Paielli;S. Brown;K. Barton;Mei Lu;E. Aguilar‐Cordova;J. H. Kim
腺病毒介导的自杀基因疗法可能有望治疗人类癌症。我们开发了一种新方法，利用具有裂解性、复制能力的腺病毒 (Ad5-CD/TKrep) 将胞嘧啶脱氨酶/单纯疱疹病毒-1 胸苷激酶融合基因递送至肿瘤。胞嘧啶脱氨酶和单纯疱疹病毒-1胸苷激酶自杀基因使恶性细胞对特定药物敏感，更重要的是，使它们对辐射敏感。这里描述的第一阶段研究代表了第一个基因治疗试验，其中使用具有复制能力的病毒向人类传递治疗基因。适应症是明确的放射治疗后前列腺癌的局部复发。在经直肠超声引导下，将 Ad5-CD/TKrep 病毒的剂量递增（10(10)、10(11) 和 10(12) 病毒颗粒）注射到 4 个队列中的 16 名患者的前列腺内。两天后，患者接受 5-氟胞嘧啶和更昔洛韦前药治疗 1（第 1-3 组）或 2（第 4 组）周。没有剂量限制性毒性，并且 Ad5-CD/TKrep 载体的最大耐受剂量没有定义。观察到的 94% 的不良事件性质为轻度或中度（1/2 级）。 16 名患者中的 7 名 (44%) 表现出血清前列腺特异性抗原降低 > 或 = 25%，16 名患者中的 3 名 (19%) 表现出血清前列腺特异性抗原降低 > 或 = 50%。两周时通过前列腺六分仪针活检证实了注射部位的转基因表达和肿瘤破坏。两名患者在 1 年随访时腺癌呈阴性。尽管 Ad5-CD/TKrep 病毒 DNA 最早可在第 76 天在血液中检测到，但在患者血清或尿液中未检测到传染性腺病毒。总之，结果表明，前列腺内给予具有复制能力的 Ad5-CD/TKrep 病毒，然后进行 2 周的 5-氟胞嘧啶和更昔洛韦前药治疗，可以安全地应用于人类，并且显示出生物活性的迹象。
Adenovirus-mediated suicide gene therapy may hold promise in the treatment of human cancer. We have developed a novel approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/TKrep) to deliver a cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion gene to tumors. The cytosine deaminase and herpes simplex virus-1 thymidine kinase suicide genes render malignant cells sensitive to specific pharmacological agents and, importantly, sensitize them to radiation. The Phase I study described here represents the first gene therapy trial in which a replication-competent virus was used to deliver a therapeutic gene to humans. The indication is local recurrence of prostate cancer after definitive radiation therapy. An escalating dose (10(10), 10(11), and 10(12) viral particles) of the Ad5-CD/TKrep virus was injected intraprostatically under transrectal ultrasound guidance into 16 patients in four cohorts. Two days later, patients were given 5-fluorocytosine and ganciclovir prodrug therapy for 1 (cohorts 1-3) or 2 (cohort 4) weeks. There were no dose-limiting toxicities, and the maximum tolerated dose of the Ad5-CD/TKrep vector was not defined. Ninety-four percent of the adverse events observed were mild or moderate (grade 1/2) in nature. Seven of 16 (44%) patients demonstrated a >or=25% decrease in serum prostate-specific antigen, and 3 of 16 (19%) patients demonstrated a >or=50% decrease in serum prostate-specific antigen. Transgene expression and tumor destruction at the injection site were confirmed by sextant needle biopsy of the prostate at 2 weeks. Two patients were negative for adenocarcinoma at 1 year follow-up. Although Ad5-CD/TKrep viral DNA could be detected in blood as far out as day 76, no infectious adenovirus was detected in patient serum or urine. Together, the results demonstrate that intraprostatic administration of the replication-competent Ad5-CD/TKrep virus followed by 2 weeks of 5-fluorocytosine and ganciclovir prodrug therapy can be safely applied to humans and is showing signs of biological activity.