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Title: Novel treatments in muscle invasive bladder cancer
Author: Maddineni, Satish B.
ISNI:       0000 0004 2688 2523
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2008
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Bladder cancer is the second commonest malignancy of the urinary tract accounting for 145,000 directly related deaths world-wide per annum. TCC accounts for the majority of bladder cancer presenting in Europe. Approximately 70-80% of all TCC is superficial at presentation. Superficial TCC presents a major healthcare issue as it is a highly recurrent and progressive disease with recurrence rates of up to 70% and pathological progression rates up to 30% depending on grade and stage of disease. Intravesical chemotherapy and immunotherapy are established adjuvant treatments in superficial TCC with the objective of reducing recurrence with chemotherapy and reducing both recurrence and progression with immunotherapy. Muscle invasive bladder cancer requires radical treatment with radiotherapy or cystectomy. Despite significant advances in surgical techniques and perioperative management, cystectomy remains a morbid procedure with the rate of cure having reached a plateau. Radical radiotherapy has undergone significant improvements in targeting and effective dose delivery over the past 3 decades. Experiments in this thesis investigate whether further improvements in radiation induced cell kill can be achieved by manipulating the epidermal growth factor receptor and its down-stream signalling cascades using the tyrosine kinase inhibitor ZD1839. In this thesis the effects of combination treatment with ZD1839 and radiotherapy in the established bladder cancer cell lines MGHU-1 and its mutant radiosensitive clone, S40b are studied. The optimisation schedule for treatment with ZD1839 was established using colony forming assays. The mechanism of action of ZD1839 was investigated using flow cytometry for analysis of cell cycle perturbations and effects on apoptosis. Further experiments were conducted to ascertain whether there was an additive or synergistic effect between ZD1839 and the established radiosensitiser Gemcitabine at the optimum treatment schedules established for both drugs using colony forming assays.
Supervisor: Not available Sponsor: Not available
Qualification Name: MD Qualification Level: Doctoral
EThOS ID:  DOI: Not available