Optimizing of the orthotopic murine bladder cancer model and its use in the evaluation for intravesical bacillus Calmette-Guerin immunotherapy

Purpose: Orthotopic tumor models are comparable to the human situation with regard to metastatic pattern. The purpose of this study was to optimize th e orthotopic murine bladder cancer model with regard to tumor take rate and to develop a model to investigate the effects of intravesical therapeutic agents on tumor progression and survival. We used this optimized model to c larify the influence of anti-inflammatory drugs on the efficacy of intraves ical BCG in bladder cancer treatment. Materials and Methods: Syngeneic bladder cancer cells (MB49) of differing c oncentration were instilled orthotopically. The intravesical catheter was p inched off after instillation and was left in place for the duration of ane sthesia. Using this method we ensured a dwelling time of 3 h and a tumor ta ke rate of 100 %. To verify whether this modification maintained its sensit ivity to topical immunotherapy, an initial tumor load of 100000 MB 49 cells was given, and mice were treated intravesically with BCG or phosphate-buff ered saline. In the next step 75 mice were randomized into 5 groups of 15 a nimals. Intravesical treatment was done with phosphate buffered saline (PBS , group 1), BCG (Group), BCG and acetylic salicylic acid (ASA, Group 3), BC C and pentoxifylline (POF, group 4) and autoclaved BCG (aBCC, group 5). Results: The modification of instillation resulted in tumor take rate of 10 0 %, independent of the number of instilled cells. Even with the highest tu mor load, BCC therapy improved survival and reduced bladder weight signific antly, as compared to PBS. PBS and aBCG had no effect on tumor growth, wher eas animals treated with viable BCG alone and in combination with POF or AS A, showed a significant reduction in bladder weight. Mice treated with BCG, BCG + ASA, BCG + POF showed a significantly higher proportion of survival Fate compared to PBS alone. Autoclaved BCG had no therapeutic efficacy. Conclusion: Modification of the orthotopic bladder tumor model (MB 49) resu lts in a tumor take rate of 100% and maintains its susceptibility to topica l immunotherapy. The efficacy of BCG therapy in murine orthotopic bladder c ancer is dependent on BCG viability and is not compromised by ASA or POF. C linical trials to evaluate the efficacy of routine ASA or POF to reduce BCG side effects in patients should be initiated.