Effects of acetylic salicylic acid and pentoxifylline on the efficacy of intravesical BCG therapy in orthotopic murine bladder cancer (MB49)

Purpose: Intravesical immunotherapy with bacillus Calmette-Guerin (BCC), wh ich has become the gold standard in the adjuvant treatment of superficial b ladder cancer, is hampered by local side effects. Anti-inflammatory drugs m ay be helpful, but as an undesired side effect, therapeutic efficacy of BCG might be impaired. Therefore, we investigated the effects of anti-inflamma tory drugs on the efficacy of intravesical BCG in an animal model. Materials and Methods: Syngenic tumor cells were implanted into the bladder s of 75 mice according to our modification of the method, Mice were randomi zed to 5 groups with 15 animals each and treated with phosphate buffered sa line (PBS), group 1; BCG, group 2; BCG + acetylic salicylic acid (ASA), gro up 3; BCG + pentoxifylline (POF), group 4; autoclaved BCG (aBCG), group 5. Intravesical instillation of 1.35 mg. BCG was initiated one day after tumor inoculation and repeated in weekly intervals for 4 instillations altogethe r. ASA and POF in doses of 200 mg./kg. and 150 mg./kg., respectively, were given continuously with the drinking water starting at, the first instillat ion. Autoclaved BCG served as control for the importance of viability and w as given at the same dose as viable BCG. Mice were monitored for survival, gross hematuria and body weight and after 28 days evaluated for bladder wei ght and tumor occurrence. Results: Autoclaved BCG and PBS had no effect on tumor growth, whereas anim als treated with viable BCG alone and in combination with POF and ASA, resp ectively, showed a significant reduction in bladder weight: PBS, 248 mg.; B CG, 140 mg. (p = 0.0009); BCG + ASA, 123 mg. (p = 0.0001); BCCT + POF, 145 mg. (p = 0.0004); autoclaved BCC;, 283 mg. (p = 0.21). Mice treated with BC G, BCG + ASA and BCG + POF showed a significantly higher proportion of surv ival until day 28 as compared to PBS alone. Autoclaved BCG had no therapeut ic efficacy (Kaplan-Meier method/log rank test: BCG, p = 0.0053; BCG + ASA? p = 0.0044; BCC; + POF, p = 0.0027; aBCG, p = 0.33). No significant differ ences among the 3 groups treated with viable BCG, with or without anti-infl ammatory drugs, regarding bladder weight and survival were detectable. Conclusions: The efficacy of BCG therapy in murine orthotopic bladder cance r is dependent on BCG viability and is not compromised by ASA or POF. Clini cal trials to evaluate the efficacy of routine ASA or POF to reduce BCG sid e effects in patients, using self-assessment criteria, should be initiated.