In Vivo Effects of Myeloablative Alkylator Therapy on Survival and Differentiation of MGMTP140K-Transduced Human G-CSF-Mobilized Peripheral Blood Cells
dc.contributor.author | Cai, Shanbao | |
dc.contributor.author | Hartwell, Jennifer R. | |
dc.contributor.author | Cooper, Ryan J. | |
dc.contributor.author | Juliar, Beth E. | |
dc.contributor.author | Kreklau, Emi | |
dc.contributor.author | Abonour, Rafat | |
dc.contributor.author | Goebel, W. Scott | |
dc.contributor.author | Pollok, Karen E. | |
dc.contributor.department | Pediatrics, School of Medicine | en_US |
dc.date.accessioned | 2021-01-25T20:33:50Z | |
dc.date.available | 2021-01-25T20:33:50Z | |
dc.date.issued | 2006-05-01 | |
dc.description.abstract | High-intensity alkylator-based chemotherapy is required to eradicate tumors expressing high levels of O6-methylguanine DNA methyltransferase (MGMT). This treatment, however, can lead to life-threatening myelosuppression. We investigated a gene therapy strategy to protect human granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells (MPB) from a high-intensity alkylator-based regimen. We transduced MPB with an oncoretroviral vector that coexpresses MGMTP140K and the enhanced green fluorescent protein (EGFP) (n = 5 donors). At 4 weeks posttransplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, cohorts were not treated or were treated with low- or high-intensity alkylating chemotherapy. In the high-intensity-treated cohort, it was necessary to infuse NOD/SCID bone marrow (BM) to alleviate hematopoietic toxicity. At 8 weeks posttreatment, human CD45+ cells in the BM of mice treated with either regimen were EGFP+ and contained MGMT-specific DNA repair activity. In cohorts receiving low-intensity therapy, both primitive and mature hematopoietic cells were present in the BM. Although B-lymphoid and myeloid cells were resistant to in vivo drug treatment in cohorts that received high-intensity therapy, no human CD34+ cells or B-cell precursors were detected. These data suggest that improved strategies to optimize repair of DNA damage in primitive human hematopoietic cells are needed when using high-intensity anti-cancer therapy. | en_US |
dc.eprint.version | Final published version | en_US |
dc.identifier.citation | Cai, S., Hartwell, J. R., Cooper, R. J., Juliar, B. E., Kreklau, E., Abonour, R., ... & Pollok, K. E. (2006). In vivo effects of myeloablative alkylator therapy on survival and differentiation of MGMTP140K-transduced human G-CSF-mobilized peripheral blood cells. Molecular Therapy, 13(5), 1016-1026. | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/24976 | |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.isversionof | 10.1016/j.ymthe.2005.11.017 | en_US |
dc.relation.journal | Molecular Therapy | en_US |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.source | Publisher | en_US |
dc.subject | gene therapy | en_US |
dc.subject | hematopoietic stem cell | en_US |
dc.subject | NOD/SCID mice | en_US |
dc.title | In Vivo Effects of Myeloablative Alkylator Therapy on Survival and Differentiation of MGMTP140K-Transduced Human G-CSF-Mobilized Peripheral Blood Cells | en_US |
dc.type | Article | en_US |
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