The principal dose-limiting toxicity of most chemotherapeutic agents is myelosuppression. In this study we evaluated the chemoprotection conferred against alkylators by a bicistronic retroviral vector expressing the chemoresistance genes GSTA3 and DHFRL22Y. As reported herein, GID-transduced murine hematopoietic cells exhibited greater survival compared to control cells in presence of chlorambucil concentrations ranging from 5 x 10-6 M to 1 x 10-4M. After increasing the fraction of GID-expressing cells via chemoselection with TMTX and NBMPR, the level of resistance was increased by up to 2.9-fold at 5 x 10-5 M chlorambucil. GID-transduced hematopoietic cell enrichment by ex vivo chemoselection was limited, under our experimental conditions, by a marked loss of hematopoietic reconstitution ability, while in vivo chemoselection was shown to hold greater potential to selectively enrich GID-expressing blood cells. The presence of replication competent virus in the experiments makes it difficult to reach to conclusive interpretations of results. Notwithstanding the unfortunate outcome of murine leukemia that did not allow for the evaluation of GID-mediated hematopoietic chemoprotection in vivo, the promising in vitro experimental results reported here warrant further investigation of this approach.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.80298 |
| Date | January 2003 |
| Creators | Karatzas, Antonios |
| Contributors | Cournoyer, Denis (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002032430, proquestno: AAIMQ98667, Theses scanned by UMI/ProQuest. |
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