In situ gene therapy for adenocarcinoma of the prostate:: A phase I clinical trial
In situ gene therapy for adenocarcinoma of the prostate:: A phase I clinical trial
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DOI：
10.1089/10430349950018229
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发表时间：
1999-05-01
影响因子：
4.2
通讯作者：
Scardino, PT
中科院分区：
文献类型：
--
作者：
Herman, JR;Adler, HL;Scardino, PT
对于确定性放射治疗后前列腺癌局部复发的患者，目前还没有普遍认为安全有效的治疗方法。在对前体药物基因治疗进行广泛的体外和体内临床前测试后，我们进行了前列腺内注射含有单纯疱疹病毒胸苷激酶基因的复制缺陷型腺病毒（ADV）的 I 期剂量递增临床试验。 （HSV-fk）直接注射到前列腺，然后静脉注射前药更昔洛韦（GCV），我们的目标是确定载体的安全剂量水平，用于未来的疗效试验，血清前列腺特异性抗原（PSA）水平升高的患者，活检证实前列腺癌局部复发，且在明确的放射治疗一年或多年后无转移证据 符合试验资格，在给予知情同意后，患者在超声引导下接受 1 英里内浓度递增的 ADV/HSA-tk 注射，然后静脉注射更昔洛韦 14 天（每 12 小时 5 毫克/公斤），密切监测患者的毒性证据和治疗反应，18 名患者接受 4 次递增剂量治疗：第 1 组（n = 4） 收到 1 x 10(8) 感染单位 (IU)；第 2 组 (n = 5) 接受 1 x 10(9) IU；第 3 组 (n = 4) 接受 1 x 10(10) IU；第 4 组 tit = 5) 接受 1 x 10(11) IU，治疗后通过尿样 PCR 检测载体，随着剂量增加，频率和持续时间也增加（最多 32 天）。所有血液和尿液标本的腺病毒生长培养均为阴性。 4 名患者出现了最小毒性（1-2 级）。一名患者在最高剂量水平下出现自发可逆的 4 级血小板减少症和 3 级肝毒性。三名患者在三个最高剂量水平下各一名患者取得了客观缓解，记录为血清 PSA 水平下降 50% 或更多，持续 6 周至 1 年。这项研究首次证明了 ADV/HSV-tk 加 GCV 基因治疗在人类前列腺癌中的安全性，也是首次证明基因治疗在前列腺癌患者中的抗癌活性。进一步的试验正在进行中，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。
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 is 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-fk) 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 mi 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 tit = 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.