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The effect of hypoxia on cytotoxicity, uptake and DNA binding of cisplatin and novel bis(platinum) complexes in Chinese hamster ovary cells

University of British Columbia

Disagreement exists in the literature as to whether the successful antitumour agent cisplatin exhibits greater toxicity in hypoxia than in air. In this study, Chinese hamster ovary cells were incubated in clinically relevant concentrations of cisplatin for periods of up to three hours in aerobic and hypoxic environments. For all incubation times studied, cells treated in hypoxia were more sensitive to cisplatin than those treated in air. Toxicity in hypoxic cells was up to two times greater than in aerobic cells. Detection of platinum using atomic absorption spectroscopy provided resolution fine enough to characterize whole cell uptake and DNA-binding of cisplatin at these concentrations. Cells treated in hypoxia showed consistently higher levels of platinum within the cells and bound to DNA than those treated in air. Furthermore, cells treated in hypoxia showed greater toxicity perplatinum-DNA adduct and per atom of platinum bound per cell than those treated in air. Two novel bis(platinum) compounds AN-38 and AN-36, of structural formula{[Pt(malonate)(NH₃)]₂H₂N(CH₂)ƞNH₂} (n=6 and 4, respectively), were also found to be preferentially toxic to hypoxic cells, up to four times as toxic as in air (for a four hour incubation), although there was little increase in platinum uptake levels. To date, this study represents the most thorough investigation of cisplatin properties in air versus hypoxia, given that survival, whole cell uptake and DNA binding in the same cell population each showed enhanced effects in hypoxia. Suggestions of possible mechanisms explaining these data could form the basis for future studies.

Thesis/Dissertation

application/pdf

2009-01-05

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http://hdl.handle.net/2429/3371

Physics

University of British Columbia

UBCV

DSpace