Journal
MOLECULAR THERAPY
Volume 3, Issue 1, Pages 78-87Publisher
ACADEMIC PRESS INC
DOI: 10.1006/mthe.2000.0223
Keywords
hematopoietic stem cells; gene therapy; methylguanine-DNA methyltransferase; temozolomide; O-6-benzylguanine; retroviral vector; bone marrow transplantation
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Funding
- NCI NIH HHS [P30 CA21765, CA23099, CA14799] Funding Source: Medline
- NHLBI NIH HHS [P01 HL 53749] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA014799, P01CA023099, P30CA021765] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL053749] Funding Source: NIH RePORTER
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Transfer of drug resistance genes to hematopoietic stem cells offers the potential to protect cancer patients from drug-induced myelosuppression and to increase the number of gene-modified cells by in vivo selection. In this study, a retroviral vector expressing both a P140K variant of human O-6-methylguanine-DNA methyltransferase (MCMT) and an EGFP reporter gene was evaluated for stem cell protection in a murine transplant model. Mice transplanted with vector-transduced cells showed significant resistance to the myelosuppressive effects of temozolomide (TMZ), an orally administered DNA-methylating drug, and O-6-benzylguanine (BC), a drug that depletes cells of wild-type MCMT activity. Following drug treatment, increases in EGFP(+) peripheral blood cells were seen in all peripheral blood lineages, and secondary transplant experiments proved that selection had occurred at the stem cell level. In a second set of experiments in which transduced cells were diluted with unmarked cells, efficient stem cell selection was noted together with progressive marrow protection with repeated treatment courses. Altogether, these results show that P140K MCMT gene transfer can protect stem cells against the toxic effects of TMZ and Be; and that this vector/drug system may be useful for clinical myeloprotection and for in vivo selection of transduced stem cells.
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