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Title: Synergistic interaction between Cisplatin and the bioreductive drug Tirapazamine
Author: Monaghan, Jane Elizabeth
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2000
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Abstract:
The presence of low oxygen conditions (or hypoxia) in solid tumours is a major hindrance to current therapies, rendering tumour cells resistant to both radiotherapy and many chemotherapies. Tirapazamine (SR4233, Win 59074)is a benzotriazene-di-N-oxide which under hypoxic conditions is reduced to a free radical capable of abstracting hydrogen from DNA causing single and double strand DNA breaks. Tirapazamine is therefore selectively toxic towards hypoxic cells and it is currently in clinical trials in combination with cisplatin. These trials are based on pre-clinical work of Dorie and Brown (1993, 1997, Siemann et al; 1997) who demonstrated substantial synergistic interaction between these two agents both in vitro and in vivo. This synergy is schedule-dependent, and the mechanism of interaction is currently unknown. The potentiation of cisplatin cytotoxicity by tirapazamine was studied in a panel of breast carcinoma cell lines. Tirapazamine toxicity in these cell lines has been studied previously (Patterson et al 1993), and shown to correlate with P450 reductase activity, the enzyme thought to be responsible for tirapazamine metabolism. The panel of breast carcinoma cell lines has a fifty-fold range in cisplatin sensitivity, and inherent resistance to cisplatin does not confer resistance to the tirapazamine/cisplatin combination. In addition, enhancement increases in those cell lines most resistant to tirapazamine. Transfection of MDA 231 cells with p450 reductase cDNA, results in increased sensitivity to tirapazamine compared to wild type (Patterson et al; 1996), but the synergistic interaction between tirapazamine and cisplatin is not seen. The relationship between tirapazamine toxicity and metabolism by P450 reductase has also been shown in the A549 lung cancer cell line (Saunders et al 2000). A549 cells with acquired resistance to tirapazamine show dramatically suppressed levels of p450 reductase (Elwell et al 1997). Tirapazamine resistant C50 cells show no potentiation by this combination of drugs, however wild type A549 cells are sensitive to tirapazamine plus cisplatin. When C50 cells are transfected with human P450 reductase cDNA to restore wild type levels of enzyme activity, the potentiation is also restored. These results indicate that p450 reductase may be involved in the interaction between cisplatin and tirapazamine, and that effectiveness of treatment may be affected by levels of this enzyme. Ovarian cancer is routinely treated by cisplatin, and an ovarian carcinoma cell line, CH1, is extremely sensitive to the combination of drugs, whereas its counterpart with acquired resistance due to increased DNA repair capabilities (Kelland et al; 1992, O'Neill et al 1999) shows no potentiation. The role of DNA repair in these cells is further investigated by the comet assay. In conclusion, this study attempts to elucidate the mechanism of synergy between tirapazamine and cisplatin. In a clinical setting, knowledge of this mechanism may help to target treatment to those tumours which will be most responsive.
Supervisor: Stratford, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.488062  DOI: Not available
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