Polyclonal chemoprotection against temozolomide in a large-animal model of drug resistance gene therapy.
Blood
; 105(3): 997-1002, 2005 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-15494421
ABSTRACT
Incorporation of drug resistance genes into gene vectors has 2 important roles in stem cell gene therapy increasing the proportion of gene-corrected cells in vivo (ie, in vivo selection) and marrow protection to permit higher or more tightly spaced doses of chemotherapy in the treatment of malignant diseases. We studied in a clinically relevant canine model of gene therapy the P140K mutant of the drug resistance gene methylguanine methyltransferase (MGMT), which encodes a DNA-repair enzyme that confers resistance to the combination of the MGMT inhibitor O(6)-benzylguanine (O(6)BG) and nitrosourea drugs such as carmustine and methylating agents such as temozolomide. Two dogs received MGMT(P140K)-transduced autologous CD34(+)-selected cells. After stable engraftment, gene marking in granulocytes was between 3% and 16% in the 2 animals, respectively. Repeated administration of O(6)BG and temozolomide resulted in a multilineage increase in gene-modified repopulating cells with marking levels of greater than 98% in granulocytes. MGMT(P140K) overexpression prevented the substantial myelosuppression normally associated with this drug combination. Importantly, hematopoiesis remained polyclonal throughout the course of the study. Extrahematopoietic toxicity was minimal, and no signs of myelodysplasia or leukemia were detected. These large-animal data support the evaluation of MGMT(P140K) in conjunction with O(6)BG and temozolomide in clinical trials.
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Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Dacarbazina
Limite:
Animals
Idioma:
En
Revista:
Blood
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Estados Unidos