Urinary bladder carcinoma, preclinical and clinical studies on EGFR based targeting

Abstract: Radical cystectomy with bilateral pelvic lymphadenectomy is the standard treatment for muscle-invasive transitional cell carcinoma of the urinary bladder. Despite presumably localised malignancies and efficacious management about 50% of patients will die within 5 years, the majority due to metastatic disease. These cases cannot be identified during the initial staging assessment and are assumed to have micrometastases preoperatively. Thus, there is a need of improved methods for diagnosis and therapy.Tumour therapy via targeting means that specific substances carrying cytotoxic agents are transferred selectively to the tumour, directed against tumour specific membrane antigens. Targeted radionuclide therapy could be an attractive way to trace and treat small volumes of tumour ceils. Damage to the normal tissue is limited while the tumour target could be optimally sterilised.The epidermal growth factor receptor (EGFR) is known to be overexpressed in bladder. The aim of this work was to assess the possibilities for EGFR based targeting of urinary bladder carcinoma.The EGFR expression was investigated using immunohistochemical technique with a monoclonal antibody in primary tumour and concurrent metastases in 20 patients. A major part of the metastatic samples were homogeneously stained and showed a moderate to strong staining of EGFR in the cell-membranes. The expression in primary bladder tumors and metastases were quite similar.Binding, internalisation and degradation of EGF-dextran conjugates was investigated in two different bladder cancer cell lines. The EGF conjugate bound specifically to the EGFR in both and was retained intracellular and membrane-bound for longer time than EGF, which was used as control. The degradation was decreased when dextran was coupled to EGF. The binding characteristic of two different sizes of EGF-dextran conjugates in multicellular spheroids of a bladder cancer cell line was investigated. Both conjugates bound to the spheroids and showed increased binding up to 48 hours.The binding characteristic of EGF-dextran in a xenograft tumour model was investigated. The specific binding was 90-95% in a control experiment in vitro. Accumulation of the conjugate was found in the tumour xenograft but also a high uptake in the kidneys. This most probably reflected the route of excretion.To determine if intravesically administered EGF-conjungate could be selectively accumulated intumor tissue, eight patients received the conjugate intravesically followed by bladder irrigation andtransurethral resection. The uptake was followed with SPECT and the radioactivity in the biopsyspecimens from normal urothelium and tumor areas were measured in a gamma counter. The EGF-dextran conjungate showed a high uptake in tumour compared to macroscopically normal urothel.In conclusion EGFR based targeting of urinary bladder carcinoma seems promising both formetastatic and local disease.

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