Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir
Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir
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DOI：
10.1200/jco.2004.00.1883
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发表时间：
2005-11-01
影响因子：
45.3
通讯作者：
Hurwitz, RL
中科院分区：
文献类型：
--
作者：
Chévez-Barrios, P;Chintagumpala, M;Hurwitz, RL
目的评估腺病毒介导的基因治疗作为视网膜母细胞瘤儿童玻璃体中肿瘤种子治疗的可行性和安全性。患者和方法机构生物安全委员会-机构审查委员会;重组DNA咨询委员会，和美国食品和药物管理局批准的I期研究使用含有单纯疱疹胸苷激酶基因（AdV-TK）的腺病毒载体的患者内剂量递增随后全身施用更昔洛韦以治疗标准疗法难治的具有玻璃体肿瘤种植的双侧视网膜母细胞瘤。采用AdV-TK治疗玻璃体肿瘤种子，每次注射后每隔12 h静脉滴注更昔洛韦，连续7 d。1例接受10（8）个病毒颗粒（vp）治疗的患者在注射部位周围的肿瘤种子消退。眼底镜检查证实，7名接受剂量≥ 10（10）vp治疗的患者玻璃体肿瘤种子消退。毒性包括10（10）vp时的轻度炎症和10（11）vp时的中度炎症、角膜水肿和眼内压升高。1例患者在治疗后38个月无活性玻璃体肿瘤种子。结论AdV-TK联合更昔洛韦治疗儿童视网膜母细胞瘤是安全的。自杀基因疗法可能有助于治疗儿童视网膜母细胞瘤肿瘤种子在玻璃体中，视网膜母细胞瘤的耐药并发症。
Purpose To evaluate the feasibility and safety of adenovirus-mediated gene therapy as a treatment for tumor seeds in the vitreous of children with retinoblastoma.Patients and Methods An Institutional Biosafety Committee-, Institutional Review Board; Recombinant DNA Advisory Committee-, and US Food and Drug Administration-approved phase I study used intrapatient dose escalation of adenoviral vector containing a herpes simplex thymidine kinase gene (AdV-TK) followed by systemic administration of ganciclovir to treat bilateral retinoblastoma with vitreous tumor seeding refractory to standard therapies. Vitreous tumor seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites, Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days.Results Eight patients with vitreous tumor seeds were enrolled. One patient who was treated with 10(8) viral particles (vp) had resolution of the tumor seeds around the injection site. The seven patients who were treated with doses >= 10(10) vp had resolution of their vitreous tumor seeds documented by fundoscopy. Toxicity included mild inflammation at 10(10) vp and moderate inflammation, corneal edema, and increased intraocular pressure at 10(11) vp. One patient was free of active vitreous tumor seeds 38 months after therapy. There has been no evidence of extraocular spread of tumor along the needle tract in any patient.Conclusion AdV-TK followed by ganciclovir can be administered safely to children with retinoblastoma. Suicide gene therapy may contribute to the treatment of children with retinoblastoma tumor seeds in the vitreous, a resistant complication of retinoblastoma.