Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.
Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.
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发表时间：
2003-11
期刊：
影响因子：
11.2
通讯作者：
S. Freytag;H. Stricker;J. Pegg;D. Paielli;D. Pradhan;J. Peabody;M. Deperalta-Venturina;X. Xia;S. Brown;Mei Lu;J. H. Kim
中科院分区：
文献类型：
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作者：
S. Freytag;H. Stricker;J. Pegg;D. Paielli;D. Pradhan;J. Peabody;M. Deperalta-Venturina;X. Xia;S. Brown;Mei Lu;J. H. Kim
研究的主要目的是确定前列腺内给药一种具有复制能力的溶瘤腺病毒的安全性，该腺病毒含有胞嘧啶脱氨酶（CD）/单纯疱疹病毒胸苷激酶（HSV-1 TK）融合基因伴随5-氟胞嘧啶和缬更昔洛韦前体药物治疗和常规剂量三维适形放射治疗（3D-CRT）持续时间的增加，中高危前列腺癌次要目的是确定前列腺中治疗性转基因表达的持续性，并检查早期治疗后反应。在第1天，5个组群中的15名患者接受了10（12）个可复制的Ad 5-CD/TKrep腺病毒的病毒颗粒的单次前列腺内注射。两天后，患者接受5-氟胞嘧啶和缬更昔洛韦前体药物治疗1周（队列1-3）、2周（队列4）或3周（队列5），同时接受沿着70-74戈伊3D-CRT。在第2周（组群1）、第3周（组群2）和第4周（组群3）获得前列腺的六分穿刺活检，以确定转基因表达的持续性。没有剂量限制性毒性，也没有显著的治疗相关不良事件。观察到的94%的不良事件为轻度至中度和自限性。急性泌尿和胃肠道毒性与常规剂量3D-CRT的预期毒性相似。发现治疗性转基因表达在腺病毒注射后在前列腺中持续长达3周。正如接受确定性放射治疗的患者所预期的那样，所有患者的前列腺特异性抗原（PSA）均显著下降。前体药物治疗超过1周的患者的平均PSA半衰期显著短于仅接受1周前体药物治疗的患者（0.6 vs 2.0个月; P < 0.02），并且显著短于先前报道的仅接受常规剂量3D-CRT治疗的患者（2.4个月）。中位随访时间仅为9个月，10例未接受雄激素剥夺治疗的患者中有5例（50%）血清PSA ≤ 0.5 ng/ml。结果表明，复制型腺病毒介导的双自杀基因治疗可以安全地与常规剂量的3D-CRT联合治疗中高危前列腺癌患者。接受超过1周前体药物治疗的患者的PSA半衰期短于预期，这可能表明溶瘤腺病毒和/或双自杀基因治疗与放射治疗之间可能存在相互作用。
The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.