Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector.
Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector.
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消除脑肿瘤和从5-氟中胞菌素到5-氟尿嘧啶的肿瘤内转化延长的生存期，使用非延柳逆转录病毒复制载体。
DOI：
10.1093/neuonc/nor199
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发表时间：
2012-02
期刊：
影响因子：
15.9
通讯作者：
Robbins JM
中科院分区：
文献类型：
--
作者：
Ostertag D;Amundson KK;Lopez Espinoza F;Martin B;Buckley T;Galvão da Silva AP;Lin AH;Valenta DT;Perez OD;Ibañez CE;Chen CI;Pettersson PL;Burnett R;Daublebsky V;Hlavaty J;Gunzburg W;Kasahara N;Gruber HE;Jolly DJ;Robbins JM
多形性胶质母细胞瘤是最常见和最具侵袭性的高级别胶质瘤，其预后差，治疗选择少。在2种免疫活性小鼠脑肿瘤模型（CT 26-BALB/c和Tu-2449-B6 C3 F1）中，我们发现非裂解性逆转录病毒复制载体（Toca 511）可将优化的胞嘧啶脱氨酶前药活化基因稳定递送至肿瘤病灶，并在5-氟胞嘧啶（5-FC）治疗后实现长期存活。载体和5-FC的生存获益均具有剂量依赖性，Toca 511治疗后最少4个周期的5-FC给药可提供显著的生存优势。在病毒允许的CT 26-BALB/c模型中，可以通过聚合酶链反应（PCR）在广泛的水平上检测到Toca 511向其他组织（特别是淋巴组织）的传播。在Tu-2449-B6 C3 F1模型中，非肿瘤组织中的Toca 511 PCR信号低得多，并不总是观察到扩散，并且当观察到时，主要在淋巴组织中以低水平检出。载体基因组扩散的差异与B6 C3 F1小鼠中存在的更有效的抗病毒限制性元件APOBEC 3相关。尽管存在这些差异，但两种菌株均未显示出给药相关毒性的体征。这些数据支持以下概念，即在免疫活性动物中，携带前药活化基因（Toca 511）的复制型逆转录病毒载体可通过肿瘤块扩散，导致前药给药后肿瘤选择性消除，无局部或全身病理学。正在进行的Toca 511联合5-FC治疗复发性高级别胶质瘤患者的I/II期临床试验（NCT 01156584）正在研究这一概念。
Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma ( NCT01156584).
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影响因子：
56.9
作者：
Korkegian, A;Black, ME;Stoddard, BL
通讯作者：
Stoddard, BL
DOI：
10.1073/pnas.0901329106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Critchley-Thorne, Rebecca J.;Simons, Diana L.;Lee, Peter P.
通讯作者：
Lee, Peter P.
影响因子：
15.9
作者：
Mizoguchi, M;Inamura, T;Fukui, M
通讯作者：
Fukui, M
影响因子：
3.7
作者：
Low, Audrey;Okeoma, Chioma M.;Fan, Hung
通讯作者：
Fan, Hung
影响因子：
3.1
作者：
Kaushik, Deepak Kumar;Gupta, Malvika;Basu, Anirban
通讯作者：
Basu, Anirban