In vitro selection for multidrug resistance (MDR) and retroactive clinical studies have established an important role for both P-glycoprotein (P-gp) and the Multidrug Resistance-associated Protein (MRP) in conferring pleiotropic resistance to several structurally dissimilar hydrophobic drugs. Both P-gp and MRP are ABC transporters which when overexpressed in tumour cells are capable of enhancing drug efflux, resulting in a drug accumulation deficit. Paradoxically, acquisition of the MDR phenotype frequently results in newfound hypersensitivity to a different group of drugs. This thesis investigates the collateral sensitivity of the P-gp-bearing CHO cell line CH$ sp{ rm R}$ C5 to the calcium channel blocker, verapamil (VRP). In addition, the hypersensitivity of the MRP-bearing SCLC line H69AR to BSO, a depleter of glutathione (GSH), is herein examined. Although VRP clearly induced heightened levels of p53-independent apoptosis in CH$ sp{ rm R}$ C5 cells, blockage of calcium channels was not involved in the cytotoxicity of the drug. BSO clearly killed through depletion of GSH, apparently resulting in heightened levels of necrosis in H69AR cells. In both cases, decreased expression of the Bcl-2 gene appeared to result in hypersensitivity of MDR cells to the toxic effects of BSO and VRP.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.27543 |
| Date | January 1997 |
| Creators | Lincoln, Maximilian Christian. |
| Contributors | Georges, Elias (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 (Institute of Parasitology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001615731, proquestno: MQ37141, Theses scanned by UMI/ProQuest. |
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