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

TY - JOUR

T1 - Optimizing chemotherapy for transitional cell carcinoma by application of bcl-2 and bcl-xL antisense oligodeoxynucleotides.

AU - Bolenz, Christian

AU - Becker, Andreas

AU - Trojan, Lutz

AU - Schaaf, Axel

AU - Cao, Yanwei

AU - Weiss, Christel

AU - Alken, Peter

AU - Michel, Maurice Stephan

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 25

SP - 476

EP - 482

JO - UROL ONCOL-SEMIN ORI

JF - UROL ONCOL-SEMIN ORI

SN - 1078-1439

IS - 6

M1 - 6

ER -