The effectiveness of anti-cancer chemotherapy is limited by acute dose limiting toxicities, principally myelosuppression. The introduction of drug resistance genes into hematopoietic cells may increase the bone marrow (BM) tolerance to chemotherapy and may permit safer dose escalation, and thus increase clinical efficacy. Conferring chemoprotection to nitrogen mustards would be clinically relevant because of their broad spectrum of anti-tumor activity and their predominant, dose-limiting hematotoxicity. The glutathione S-transferase (GST) alpha isoenzymes, particularly the rat GSTA3, have been implicated in resistance to nitrogen mustards. To determine if retrovirus-mediated gene transfer of the rat GSTA3 (previously called GST-Yc) could be used to confer resistance to nitrogen mustards, we studied the expression of rat GSTA3 and the sensitivity to nitrogen mustards in mouse NIH 3T3 fibroblasts following either transfection or transduction of GSTA3 with a Moloney-based retrovirus vector (N2Yc). Populations of GSTA3-transduced cells and single cell-derived clones demonstrated increased glutathione (GSH) peroxidase activity (associated with the A3 subunit) and moderate in vitro resistance to chlorambucil and mechlorethamine. To address the feasibility of using rat GSTA3 gene transfer to confer chemoprotection to the hematopoietic system, we then transduced human leukemia K-562 cells and primary murine hematopoietic progenitor cells with the N2Yc retrovirus vector, Similarly to N2Yc-expressing fibroblasts, K-562 cells and clonogenic primary murine hematopoietic cells transduced with the N2Yc retrovirus vector demonstrated increased GSH peroxidase activity and moderate in vitro resistance to melphalan, chlorambucil and mechlorethamine. We next explored the possibility of conferring chemoprotection against nitrogen mustards in vivo following transplantation of mice with GSTA3-transduced BM cells. Unfortunately, we did not observed chemoprotection from chlorambucil in
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36636 |
| Date | January 1999 |
| Creators | Létourneau, Sylvain. |
| 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 | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001740238, proquestno: NQ64602, Theses scanned by UMI/ProQuest. |
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