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Date of Award

7-1999

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Professor G. Singh

Abstract

An ovarian carcinoma culture model is the focus of this investigation based on a unique association between an elevated mitochondrial membrane potential and resistance to the chemotherapeutic agent cisplatin. The model consists of the 2008 parental cell line, the C13* subline that has acquired stable resistance to cisplatin and the RH4 revertant line that has regained sensitivity to cisplatin following selection with the anti-mitochondrial agent rhodamine 123. The cumulative data for resistance mechanisms that operate in this model suggest that increased tolerance to damage is a major determinant of the overall cytotoxic response to cisplatin. We have adopted the general hypothesis that mitochondria play a role in the mediation of resistance to cisplatin, and have furthered the investigation of these cells in terms of their energetic and redox balance characteristics. No significant differences exist between 2008, C13* and RH4 cells in terms of glycolytic capacity but when assayed for mitochondrial function both the cisplatin-resistant C13* and the cisplatin-sensitive RH4 cells have a significantly reduced capacity for mitochondrial respiration. This common characteristic indicated that alterations in energy production do not influence resistance, but perhaps other associated mitochondrial activities like reactive oxygen species production could have an impact. Measurement of extracellular hydrogen peroxide (H2 O2 ) production revealed a significant increase in the C13* versus 2008 cell population, which is the result of contributions by multiple intracellular sources including mitochondria and potentially novel flavoproteins. The exact relationship between increased H2 O2 production and cisplatin resistance is not yet defined but one major implication is the evidence for extracellular H2 O2 as a required autocrine growth factor for various cultured cell lines including 2008 and C13* cells. The pro-proliferation role of H2 O2 suggests it could influence the balance of survival versus death effector signals that may have an impact on the threshold of apoptosis initiation in these cells.

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