In vivo selection of autologous MGMT gene-modified cells following reduced-intensity conditioning with BCNU and temozolomide in the dog model.
In vivo selection of autologous MGMT gene-modified cells following reduced-intensity conditioning with BCNU and temozolomide in the dog model.
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DOI：
10.1038/cgt.2012.25
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发表时间：
2012-08
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
BCNU和替莫唑胺（TMZ）的化疗通常用于治疗多形性胶质母细胞瘤（GBM）和其他癌症。在准备对胶质母细胞瘤患者进行临床基因治疗研究时，我们希望研究这些试剂是否可用作基因修饰细胞自体移植的低强度预处理方案。我们使用表达MGMT（P140 K）的慢病毒载体修饰狗CD 34+细胞，并在4只狗中测试这些自体细胞是否植入并在移植后提供化学保护。移植后用O 6-苄基鸟嘌呤（O 6 BG）/TMZ治疗导致基因标记水平高达75%，没有明显的造血细胞减少，这与造血化学保护一致。逆转录病毒整合分析表明，多个克隆有助于造血。这些研究证明了在使用BCNU和TMZ的组合的新的降低强度的预处理方案之后实现MGMT（P140 K）修饰的自体HSC的稳定植入的能力。此外，我们表明，MGMT（P140 K）-HSC移植在TMZ剂量递增期间提供化学保护。在临床上，BCNU和TMZ的化学预处理应促进MGMT（P140 K）修饰细胞的植入，同时为预后不良的胶质母细胞瘤或烷化剂敏感性肿瘤患者提供抗肿瘤活性，从而支持剂量强化化疗方案。
Chemotherapy with BCNU and temozolomide (TMZ) is commonly used for the treatment of glioblastoma multiforme (GBM) and other cancers. In preparation for a clinical gene therapy study in patients with glioblastoma, we wished to study whether these reagents could be used as a reduced-intensity conditioning regimen for autologous transplantation of gene-modified cells. We used an MGMT(P140K)-expressing lentivirus vector to modify dog CD34+ cells and tested in 4 dogs whether these autologous cells engraft and provide chemoprotection after transplantation. Treatment with O6-benzylguanine (O6BG)/TMZ after transplantation resulted in gene marking levels up to 75%, without significant hematopoietic cytopenia, which is consistent with hematopoietic chemoprotection. Retrovirus integration analysis showed that multiple clones contribute to hematopoiesis. These studies demonstrate the ability to achieve stable engraftment of MGMT(P140K)-modified autologous HSCs after a novel reduced-intensity conditioning protocol using a combination of BCNU and TMZ. Furthermore, we show that MGMT(P140K)-HSC engraftment provides chemoprotection during TMZ dose escalation. Clinically, chemoconditioning with BCNU and TMZ should facilitate engraftment of MGMT(P140K)-modified cells while providing anti-tumor activity for patients with poor prognosis glioblastoma or alkylating agent sensitive tumors, thereby supporting dose-intensified chemotherapy regimens.
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影响因子：
4.1
作者：
McGirt MJ;Than KD;Weingart JD;Chaichana KL;Attenello FJ;Olivi A;Laterra J;Kleinberg LR;Grossman SA;Brem H;Quiñones-Hinojosa A
通讯作者：
Quiñones-Hinojosa A
影响因子：
14.2
作者：
Fischer, Alain;Hacein-Bey-Abina, Salima;Cavazzana-Calvo, Marina
通讯作者：
Cavazzana-Calvo, Marina
影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L
影响因子：
12.4
作者：
Budak-Alpdogan, T;Alpdogan, O;Bertino, JR
通讯作者：
Bertino, JR
影响因子：
20.3
作者：
Horn, PA;Keyser, KA;Kiem, HP
通讯作者：
Kiem, HP