Journal
GENE THERAPY
Volume 17, Issue 3, Pages 389-399Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2009.133
Keywords
chemoprotection; hematopoietic stem cells; lentiviral vector; MDR1; MGMT(P140K)
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Funding
- Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung [10-2089-FI 1]
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Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O-6-benzylguanine (O-6-BG)-resistant mutant MGMT(P140K) (O-6-methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR'SIN-MDR1-IRES-MGMT(P140K)), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34(+)). Combination therapy with O-6-BG/1-(2-chloroethyl)-3-(4-amino-2-methyl pyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34(+) cells, monotherapy with O-6-BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR0SIN-MDR1-IRES-MGMT(P140K) (28.3%). For combination therapy with O-6-BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMT(P140K) solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR'SIN-MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O-6-BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drug-resistance genes, offering an opportunity to increase the cancer therapeutic index. Gene Therapy (2010) 17, 389-399; doi:10.1038/gt.2009.133; published online 29 October 2009
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