Herman J R, Adler H L, Aguilar-Cordova E, Rojas-Martinez A, Woo S, Timme T L, Wheeler T M, Thompson T C, Scardino P T
Scott Department of Urology, Matsunaga-Conte Prostate Cancer Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
Hum Gene Ther. 1999 May 1;10(7):1239-49. doi: 10.1089/10430349950018229.
For patients with local recurrence of prostate cancer after definitive irradiation therapy there is no treatment widely considered safe and effective. After extensive preclinical testing of prodrug gene therapy in vitro and in vivo, we conducted a phase I dose escalation clinical trial of intraprostatic injection of a replication-deficient adenovirus (ADV) containing the herpes simplex virus thymidine kinase gene (HSV-tk) injected directly into the prostate, followed by intravenous administration of the prodrug ganciclovir (GCV). Our goal was to determine safe dose levels of the vector for future trials of efficacy. Patients with a rising serum prostate-specific antigen (PSA) level and biopsy confirmation of local recurrence of prostate cancer without evidence of metastases one or more years after definitive irradiation therapy were eligible for the trial. After giving informed consent, patients received injections of increasing concentrations of ADV/HSA-tk in 1 ml into the prostate under ultrasound guidance. Ganciclovir was then given intravenously for 14 days (5 mg/kg every 12 hr). Patients were monitored closely for evidence of toxicity and for response to therapy. Eighteen patients were treated at 4 escalating doses: group 1 (n = 4) received 1 x 10(8) infectious units (IU); group 2 (n = 5) received 1 x 10(9) IU; group 3 (n = 4) received 1 x 10(10) IU; group 4 (n = 5) received 1 x 10(11) IU. Vector was detected by PCR of urine samples after treatment, increasing in frequency and duration (up to 32 days) as the dose increased. All cultures of blood and urine specimens were negative for growth of adenovirus. Minimal toxicity (grade 1-2) was encountered in four patients. One patient at the highest dose level developed spontaneously reversible grade 4 thrombocytopenia and grade 3 hepatotoxicity. Three patients achieved an objective response, one each at the three highest dose levels, documented by a fall in serum PSA levels by 50% or more, sustained for 6 weeks to 1 year. This study is the first to demonstrate the safety of ADV/HSV-tk plus GCV gene therapy in human prostate cancer and the first to demonstrate anticancer activity of gene therapy in patients with prostate cancer. Further trials are underway to identify the optimal distribution of vector within the prostate and to explore the safety of repeat courses of gene therapy.
对于接受确定性放射治疗后前列腺癌局部复发的患者，尚无被广泛认为安全有效的治疗方法。在对前药基因疗法进行了广泛的体外和体内临床前测试后，我们开展了一项I期剂量递增临床试验，将携带单纯疱疹病毒胸苷激酶基因（HSV-tk）的复制缺陷型腺病毒（ADV）直接注射到前列腺内，随后静脉注射前药更昔洛韦（GCV）。我们的目标是确定该载体在未来疗效试验中的安全剂量水平。确定性放射治疗后一年或更长时间，血清前列腺特异性抗原（PSA）水平升高且经活检证实前列腺癌局部复发但无转移证据的患者符合该试验条件。在获得知情同意后，患者在超声引导下接受将浓度递增的ADV/HSV-tk 1 ml注射到前列腺内。然后静脉注射更昔洛韦14天（每12小时5 mg/kg）。密切监测患者的毒性证据和对治疗的反应。18名患者接受了4个递增剂量的治疗：第1组（n = 4）接受1×10⁸感染单位（IU）；第2组（n = 5）接受1×10⁹ IU；第3组（n = 4）接受1×10¹⁰ IU；第4组（n = 5）接受1×10¹¹ IU。治疗后通过尿液样本的PCR检测到载体，其频率和持续时间（长达32天）随剂量增加而增加。所有血液和尿液标本培养均未检测到腺病毒生长。4名患者出现轻微毒性（1 - 2级）。1名最高剂量组的患者出现了自发可逆的4级血小板减少和3级肝毒性。3名患者获得了客观缓解，分别在三个最高剂量组各有1名，表现为血清PSA水平下降50%或更多，并持续6周至1年。本研究首次证明了ADV/HSV-tk加GCV基因疗法在人类前列腺癌中的安全性，也是首次证明基因疗法在前列腺癌患者中的抗癌活性。正在进行进一步试验以确定载体在前列腺内的最佳分布，并探索重复基因治疗疗程的安全性。
