Thomas, David James; (1995) Determinants of chemosensitivity in transitional cell carcinoma of the bladder. Masters thesis (M.Surg), UCL (University College London).

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Abstract

Transitional cell carcinoma of the bladder is sensitive to combination chemotherapy and response rates of up to 65% have been reported. However, 35% of cases do not respond and relapse is common. The reasons for treatment failure are unclear. One possible mechanism is the presence of innate drug resistance within tumours and another is potential variation in cytotoxic drug levels, resulting in underdosing of some patients. These two possibilities have been explored. In this thesis two drug resistance mechanisms have been studied. Firstly expression of the enzyme Glutathione S-transferase π, which conjugates cytotoxic agents to glutathione, has been measured in a series of tumours. Levels of enzyme expression have been related to outcome in a group of patients who went on to receive cisplatin based chemotherapy. No difference was demonstrated, in terms of enzyme expression between tumours that had responded to chemotherapy and those that had not. Secondly a semi-quantitative, polymerase chain reaction based, assay has been developed in order to measure expression of the multidrug resistance gene (MDR1) at the mRNA level. This has involved amplifying the MDR1 gene relative to an internal reference gene, namely ribosomal RNA. Using this assay a 63 fold variation in MDR1 mRNA levels was demonstrated between tumours with a significantly higher level in poorly differentiated tumours. A total of 57 pharmacokinetic studies were performed on 30 patients with transitional cell carcinoma receiving combination chemotherapy. Wide variations were observed in cytotoxic drug levels achieved and free cisplatin levels were significantly higher in the group of patients demonstrating a clinical response to treatment when compared to levels achieved in non-responders. The studies performed in this thesis have revealed the limitations of current cytotoxic dosing methods. The wide variation in MDR1 expression suggests that classical multidrug resistance may be a significant mechanism in chemotherapy failure in the treatment of transitional cell carcinoma of the bladder.

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