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411 Development of Cross-Resistance in Urothelial Cancer Cell Lines with Acquired Resistance Against Gemcitabine and Cisplatin

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411 Development of Cross-Resistance in Urothelial Cancer Cell Lines with Acquired Resistance Against Gemcitabine and Cisplatin 411 Development of cross-resistance in urothelial cancer cell lines with acquired resistance against gemcitabine and cisplatin. Is chemo- or radiation-therapy still working? Eur Urol Suppl 2014;13;e411 Print! Vallo S.1, Michaelis M.2, Bartsch G.1, Rödel F.3, Haferkamp A.1, Cinatl J.4 1University Hospital Frankfurt, Dept. of Urology, Frankfurt am Main, Germany, 2University of Kent, Dept. of Molecular Processing and School of Biosciences, Canterbury, United Kingdom, 3University Hospital Frankfurt, Dept. of Radiation Therapy and Oncology, Frankfurt am Main, Germany, 4University Hospital Frankfurt, Dept. of Virology, Frankfurt am Main, Germany INTRODUCTION & OBJECTIVES: Metastatic or advanced urothelial cancer is still associated with a poor prognosis. Combination- chemotherapy with gemcitabine and cisplatin is standard of care with a long-term survival of only 12-14 months. Here, we used 18 different chemotherapeutic substances with different modes of action as a treatment in 6 different parental urothelial cancer cell lines, 6 corresponding gemcitabine-resistant sublines and 6 cisplatin-resistant sublines to identify promising new second-line chemotherapy regimens. In addition, the influence of acquired chemoresistance on the cancer cell sensitivity to radiotherapy was investigated. MATERIAL & METHODS: The drug-resistant sub-lines were established by continuous exposure to increasing drug concentrations. Cell viability was investigated by MTT assay. Growth characteristics were determined by daily cell counting. Effects of radiation were detected by clonogenic survival assay. RESULTS: The most effective compounds were vinflunine, vinblastine, and topotecan that exerted in 11 of the 12 investigated cisplatin- or gemcitabine-resistant urothelial carcinoma cell lines similar effects like those detected in the respective parental cell lines. Cabazitaxel, larotaxel and mitomycin c were effective in 10 of 12 resistant urothelial carcinoma sub-lines. In contrast, 8 of the 12 investigated resistant cell lines displayed cross-resistance to carboplatin, 5 of the 12 resistant cell lines displayed cross-resistance to pemetrexed, and 4 of 12 cell lines displayed cross-resistance to methotrexate. Cell lines originally from papillary and less agressiv tumours like RT4 and 5637 had a reduced affinity to develop cross-resisnce against gemcitabine and cisplatin. In general, resistance acquisition to gemcitabine was associated with a more pronounced cross-resistance phenotype than resistance acquisition to cisplatin. Moreover, resistance acquisition to gemcitabine resulted in decreased radiation sensitivity in 3 of 6 resistant sublines and resistance acquisition to cisplatin in 2 of 6 sublines. CONCLUSIONS: Vinca alkaloids like vinblastine and vinflunine as well as topotecan seem to be effective therapeutic options in patients with advanced urothelial carcinoma who are pretreated with gemcitabine and cisplatin..
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