Optimizing chemotherapy for transitional cell carcinoma by application of bcl-2 and bcl-xL antisense oligodeoxynucleotides

• Published in: Urologic oncology 2007-11, Vol.25 (6), p.476-482
• Main Authors: Bolenz, Christian, M.D, Becker, Andreas, Trojan, Lutz, M.D., M.Sc, Schaaf, Axel, Ph.D, Cao, Yanwei, M.D, Weiss, Christel, M.D, Alken, Peter, M.D., Ph.D, Michel, Maurice Stephan, M.D., Ph.D
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic combined chemotherapy protocols; Antisense oligodeoxyribonucleotides; bcl-X Protein - antagonists & inhibitors; Biological and medical sciences; Bladder neoplasms; Blotting, Western; Carcinoma, Transitional Cell - drug therapy; Cell Line, Tumor; Chemotherapy; Cisplatin - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Immunohistochemistry; Medical sciences; Mitomycin - pharmacology; Nephrology. Urinary tract diseases; Oligoribonucleotides, Antisense; Paclitaxel - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Transitional cell carcinoma; Tumors; Urinary Bladder Neoplasms - drug therapy; Urology
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2007.01.017

Abstract Objective Therapy failure after intravesical and systemic chemotherapy for transitional cell carcinoma (TCC) is still high. Antiapoptotic proteins such as Bcl-2 and Bcl-xL have been reported to promote chemoresistance in TCC. Targeting bcl-2 and bcl-xL messenger ribonucleic acid with antisense oligodeoxynucleotides (AS-ODNs) may enhance the cytotoxic effects of chemotherapeutic agents. Therefore, we investigated the effects of bcl-2 and bcl-xL AS-ODNs in combined treatment with conventional and new chemotherapeutic agents to evaluate the cytotoxic effects in comparison to monotreatment. Methods and materials Western blot analysis or immunohistochemistry verified Bcl-2 and Bcl-xL expression in a panel of human TCC cell lines that had been monotreated with cisplatin, gemcitabine, mitomycin C, and paclitaxel. In addition, bcl-2 or bcl-xL AS-ODNs were applied in combination with each chemotherapeutic agent. Cell viability was determined using a standard MTT assay and Neubauer hemocytometry. Results All cell lines responded to chemotherapeutic monotreatment in a dose-dependent manner. Maximum cell death rates after monotreatment were 47.4% (cisplatin), 39.0% (gemcitabine), 83.4% (mitomycin C), and 54.8% (paclitaxel). After combined treatment with chemotherapy and bcl-2 or bcl-xL AS-ODNs, cell death rates were significantly higher (e.g., 30.3% vs. 87.2% in HT 1197 cells for monotreatment vs. the combination of paclitaxel and bcl-xL AS-ODNs). Three-way analysis of variance revealed that combined treatment had a significant effect on all cell lines. Conclusions Our study confirms that the addition of bcl-2 and bcl-xL AS-ODNs enhances the cytotoxic potential of chemotherapeutic agents in TCC cell lines as a result of combined effects. Further trials in ex vivo and in vivo models have to be performed to promote clinical application in patients.