A study of an effective sunitinib–chemotherapeutic combination regimen for bladder cancer treatment using a mouse model

ObjectiveTo determine if tyrosine kinase receptor inhibitor, sunitinib malate, combined with chemotherapeutic drugs may present synergistic enhancement of cytotoxicity to transitional cell carcinoma cells (TCC).MethodsThe mRNA and protein contents of vascular endothelial growth factor-α (VEGFα) in various TCC cell lines were detected individually by quantitative-polymerase chain reaction and Western blot. The inhibitory concentrations of various chemotherapeutic drugs, including gemcitabine, doxorubicin, and cisplatin, and their combination with sunitinib to TCC cancer cells were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The synergist efficacy was measured using the observed/expected ratio calculation method. Finally, the synergistic effect of sunitinib and selected anticancer drug gemcitabine was elucidated in C3H/MBT-2 animal tumor model with monitoring tumor growth volume and survival rate.ResultsThe mRNA of VEGFα had high expression in high-grade TCC cell lines (T24, TCC 8701, and TCC 8702) when compared with low-grade TCC cell lines (TCC 8301 and TSGH 9201). The expression of VEGFα protein level was closely correlated with the mRNA content in each individual cell line. Sunitinib, combined with gemcitabine, has shown the highest synergistic cytotoxic effect to TCC cells in an MTT assay. In the xenografted tumor model, MBT-2 bearing mice treated by sunitinib and gemcitabine combination had the lower mean tumor volume (265 ± 95 mm3 vs. 2605 ± 320 mm3) and higher survival rate (100% vs. 56%) at 30 days follow-up when compared with control mice.ConclusionCombination of the tyrosine kinase receptor inhibitor sunitinib with gemcitabine chemotherapy synergistically enhances tumor cytotoxicity and may provide a new treatment modality for advanced bladder cancer.