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 Blood, 1 February 2005, Vol. 105, No. 3, pp. 997-1002.
Prepublished online as a Blood First Edition Paper on October 19, 2004; DOI 10.1182/blood-2004-08-3169.

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GENE THERAPY

Polyclonal chemoprotection against temozolomide in a large-animal model of drug resistance gene therapy

Tobias Neff, Brian C. Beard, Laura J. Peterson, Ponni Anandakumar, Jesse Thompson, and Hans-Peter Kiem

From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Department of Medicine, University of Washington, Seattle, WA.

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 O6-benzylguanine (O6BG) 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 O6BG 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 O6BG and temozolomide in clinical trials.


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