The objective of this thesis was to determine whether altered transport of a novel sarcosinamide analog of chloroethylnitrosourea (SarCNU) may account for its increased antitumor activity in primary and established glioma cells as compared to BCNU, the agent of choice for chemotherapy of brain tumors. These studies were done in the SarCNU-sensitive SK-MG-1 glioma cells and the 20-fold more resistant SKI-1 cells. Indirect evidence for a sarcosinamide-related uptake for SarCNU was obtained by using cytotoxicity as an indicator for transport in SK-MG-1 cells. The transport of radiolabelled sarcosinamide was shown to proceed via facilitated diffusion, an energy-independent, carrier-mediated process which also accommodates SarCNU. Epinephrine was identified as the native substrate for this uptake which is similar to the catecholamine uptake 2. The source of resistance to SarCNU in SKI-1 cells was also examined. The decreased steady-state accumulation of SarCNU shown in SKI-1 cells was not secondary to the observed alterations in the kinetics of SarCNU transport in these cells. The decrease in SarCNU-induced DNA crosslinks noted in SKI-1 cells was neither a result of increased expression of ERCC-1 RNA nor repair by the O$ sp6$-alkylguanine DNA transferase nor the 3-methyladenine DNA glycosylase activity. The slight elevation of glutathione transferase (GST) mu RNA in SKI-1 cells suggests that detoxification may contribute to resistance. These results indicate that resistance to SarCNU may be mediated by increased drug efflux and/or alternative DNA repair in SKI-1 cells.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74255 |
| Date | January 1989 |
| Creators | Skalski, Violetta |
| 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: 001068862, proquestno: AAINN63401, Theses scanned by UMI/ProQuest. |
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