Beschreibung:
<jats:p> 261 </jats:p><jats:p> Background: Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. Despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Methods: A panel of 10 urothelial cancer cell lines was exposed to gemcitabine and cisplatin, a Smac mimetic, and the combination. Sensitivity was determined using a DNA fragmentation assay. Constitutive expression of select members of the IAP family (XIAP, cIAP-1, cIAP-2, Survivin), the BCL family (BCL-2, BCL<jats:sub>XL</jats:sub>, BAX) and Smac were evaluated by gene expression profiling and Western blotting. Changes in protein expression under treatment conditions were examined using Western blotting. TNF-a blocking antibody was used to explore the contribution of autocrine TNF-a in cellular death. Lastly, a mouse model of bladder cancer was used to determine the effectiveness of the drug combination. Results: UMUC-3, UMUC-13 and RT4v6 were considered sensitive to the combination of gemcitabine and cisplatin based on an apoptosis assay. Three additional cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, UMUC-18). The constitutive RNA and protein expression of SMAC, select members of the IAP family, and members of the BCL family did not correlate to drug sensitivity. Autocrine TNF-a demonstrated a partial contribution to cell death in UMUC-12. In an in vivo mouse model, the Smac mimetic alone and in combination with gemcitabine and cisplatin resulted in decreased tumor volume and increased apoptosis compared to the chemotherapy treatment alone. The combination resulted in decreased cellular proliferation and decreased microvessel density. Conclusions: Smac mimetic is able to augment the activity of gemcitabine and cisplatin based chemotherapy in vitro and in vivo. This may be an effective treatment strategy in patients with urothelial carcinoma and warrants further investigation. </jats:p>