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Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP093) RAD51: A DNA repair target for increasing the therapeutic potential in the treatment of bladder cancer.

Choudhury, Ananya*,1, 2, Jalali, Farid1, Kiltie, Anne 2, Bristow, Robert *,1, 1 Dept. of Radiation Oncology and Medical Biophysics, Toronto, Ontario, Canada2 Division of Cancer Medicine Research, Leeds, West Yorkshire, UK

ABSTRACT- INTRODUCTION: Organ preservation for T2-T4 staged bladder cancer using concurrent chemotherapy and radiotherapy (XRT) is an important treatment modality. Complete response rates upwards of 70-80% can be achieved in appropriately selected patients. Chemoresistance to gemcitabine and cisplatin (two active agents in bladder cancer) has been linked to overexpression of RAD51, a protein involved in the homologous recombination (HR) DNA-dsb repair pathway. Therapeutic manipulation of RAD51 expression, or RAD51 signaling pathways, may allow increased chemo-radiosensitization within a favorable therapeutic ratio. We hypothesize that manipulation of the HR-RAD51 pathway could lead to a therapeutic gain for bladder cancers treated with XRT-cisplatin or XRT-gemcitabine. METHODS & RESULTS: Using the RT112 bladder-TCC cell model, clonogenic survival has been initially determined for cell exposure to ionizing radiation, gemcitabine, cisplatin and mitomycin C (the latter used to measure relative HR). RT-112 cells were observed to have an intact ATM-p53 checkpoint based on elevated levels of p53, p21WAF following 2 and 10Gy. Treatment of cells with RAD51 siRNA led to dose-dependent decreases in RAD51 RNA and protein expression at 24-72 hrs and altered RAD51 intranuclear foci formation. Decreased RAD51 protein was also observed following a 24 hr treatment with Gleevec (5-15 uM; an inhibitor of c-ABL/RAD51 signaling), pre- and post-radiation. Data from current experiments correlating decreased RAD51 signaling, apoptosis and cell cycle changes to combined drug-radiation cell kill in RT-112 cells, tert-immortalized bladder urothelial cells and GM5757 normal diploid fibroblasts will be presented. CONCLUSIONS: RAD51 inhibition may be a novel strategy to increase the radiosensitization of bladder cancer if it translates to maximal sensitization of bladder tumour cells over that of normal tissues. This may allow for novel treatment strategies that increase organ-preservation rates and quality of life for bladder cancer patients.

Key words: Rad51, Bladder cancer, Gleevec, chemoradiosensitization


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2005 RRS