Previous work demonstrated that influx of (2-chloroethyl)-1-sarcosinamide-1-nitrosourea (SarCNU) may be altered from the known influx of clinically available chloroethylnitrosoureas which occurs through passive diffusion. The objective of this thesis was to determine the exact mode of influx of SarCNU into human glioma cell lines SK-MG-1 and SKI-1 which are sensitive and resistant to SarCNU, respectively. The influx of SarCNU into SK-MG-1 cells was shown to be mediated by a saturable, energy and sodium independent epinephrine sensitive carrier system. Analysis of influx of SarCNU into SKI-1 cells demonstrated a technically non-saturable mechanism of entry consistent with passive diffusion. Steady-state accumulation of SarCNU was demonstrated to be greater in SK-MG-1 cells versus SKI-1 cells at 37$ sp circ$C whereas there was similar accumulation at 22$ sp circ$C. Differences in steady-state accumulation were not attributable to altered metabolism or efflux. Increased accumulation of SarCNU in SK-MG-1 cells at 37$ sp circ$C was identified to be a consequence of an increased initial rate of influx at 37$ sp circ$C in SK-MG-1 cells versus SKI-1 cells with no significant difference at 22$ sp circ$C. Analysis of chloroethylnitrosourea sensitivity revealed that SKI-1 cells were 3 fold resistant versus SK-MC-1 to SarCNU at 37$ sp circ$C but only 2 fold resistant at 22$ sp circ$C with no temperature shift effect on the 2 fold level of resistance to BCNU. A more detailed analysis of the SarCNU carrier involving the analysis of norepinephrine influx revealed that SarCNU influx into SK-MG-1 cells occurs through the extraneuronal catecholamine uptake$ sb2$ transporter which is not detectable in SKI-1 cells. This is the first direct demonstration of the presence of the uptake$ sb2$ transporter in a human glioma cell line. These findings suggest that increased sensitivity of SK-MG-1 cells to SarCNU is secondary to enhanced accumulation of SarCNU mediated via the uptake$ sb2$ t
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.40413 |
| Date | January 1996 |
| Creators | Noë, Adrian J. (Adrian James) |
| Contributors | Panasci, Lawrence C. (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: 001528944, proquestno: NN19758, Theses scanned by UMI/ProQuest. |
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