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Title: Platinum chemotherapy : investigation of cellular resistance mechanisms and early development of an oral analogue
Author: Nicolson, Marianne Coutts
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1996
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In this thesis, the results are presented of experiments performed to investigate the mechanisms of platinum resistance in the murine L1210 leukaemia cell line in vitro. In addition, platinum resistant L1210 variants have been developed and these cell lines are also studied. In addition to allowing characterisation of the resistant cells, murine and human tumour models are invaluable in screening novel compounds for antitumour activity. In the second part of the thesis, the L1210 sensitive and resistant cell lines are employed along with human ovarian cancer cell lines in vitro to screen several compounds which are structurally related to the parent platinum drugs cisplatin, carboplatin, tetraplatin and iproplatin. The aim of the work was to identify compounds which demonstrated cytotoxic activity against cell lines which were known to be platinum resistant. The mixed amine platinum IV dichlorodicarboxylates were selected and data on their in vitro activities are presented. The six leading novel compounds were also tested for relative activity against the plasmacytoma tumour ADJ/PC6 in murine xenografts, and their relative activities and toxicities when delivered by the oral or the intraperitoneal route were investigated. Finally, the pharmacokinetic profiles of the six lead compounds were studied in non-tumour bearing mice following oral delivery. The haematological toxicities are also presented from experiments in the murine model. On completion of the initial studies detailed in this thesis, further experiments have resulted in selection of one of the six compounds, JM216, as a suitable candidate for evaluation in the clinic as an oral platinum antitumour agent.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available