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Title: Molecular mechanisms of bioreductive drug activation in solid tumour tissue
Author: Spanswick, Victoria Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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The enzymology of mitomycin C bioactivation was studied in vitro in two solid mouse adenocarcinomas of the colon MAC 16 (high DTD) and MAC 26 (low DTD). Metabolism of mitomycin C by tumour subcellular fractions revealed a novel mitochondrial reductase active under hypoxia in both tumours. DTD and NADPH:cytochrome P-450 reductase activity was confirmed in MAC 16 but not MAC 26. The role of DTD was examined in a tumour homogenate system and was found to play a protective role under hypoxia in MAC 16, predominating over the other enzymes present. MAC 26 showed enhanced hypoxic metabolism due to the presence of the mitochondrial reductase. The studies were extended to a human perspective, using the human colon xenografts HT-29 (high DTD) and BE (low DTD). In vivo studies, again using the MAC tumours, revealed comparable mitomycin C metabolism and antitumour activity in both tumours. Such a result has profound implications on the use of DTD as a target of enzyme-directed bioreactive drug therapy with mitomycin C. The mitomycin C analogue indoloquinone EO9 is a promising new bioreactive drug, although little is known about its metabolism and mechanism of action. The chemical properties of the reactive intermediates of EO9 were studied under controlled conditions via pulse radiolysis, with the aim of proposing a mechanism for its cytotoxicity. Results indicated that whether EO9 undergoes reduction via one-or two-electron reduction, the hydroquinone intermediate, product of two electron reduction via enzymes such as DTD, will predominate and dictate the pattern of cytotoxicity. This suggests a central role of DTD. In vitro metabolism of EO9 by the tumours described above produced a number of metabolites which proved difficult to identify via liquid-chromatography-mass spectroscopy. Unlike mitomycin C and its principle metabolite 2,7-diaminomitosene, no metabolite was found to correlate with metabolic activation under varying oxic and hypoxic conditions in conjunction with DTD activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available