Evaluation of recombinant bacillus Calmette-Guerin expressing pertussis toxin in bladder cancer.

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Author(s): D. C. Chade, R. Borra, K. R. Leite, F. E. Villanova, I. Nascimento, L. C. Liete, M. Srougi, P. M. Andrade; University of Sao Paulo, São Paulo; Ibirapuera University, São Paulo, Brazil; University of Sao Paulo, São Paulo, Brazil



Background: Pertussis toxin (S1PT) was combined to BCG, creating a recombinant variant (rBCG-S1PT) with the capacity to promote an immune response targeted to the T helper type 1 (Th1), which may increase the effectiveness of its antitumor effect.


Objective: Compare the antitumor effects of rBCG-S1PT and BCG in an experimental model of bladder cancer.


Methods: The development of the animal model of bladder cancer was conducted by transurethral instillation of bladder tumor cell line MB49 of the mouse strain C57BL/6. The animal models were divided into three groups, which received 4 weekly intravesical applications of rBCG-S1PT, BCG, or saline. After 7 days of the last instillation, bladders were extracted and weighed in order to infer the tumor weight. Then, the bladders were divided for molecular analysis to assess the pattern of immune response and histopathological analysis. In another experiment, animals were monitored for 60 days for analysis of survival. Also, a test was carried out as previously described, but with no tumor cells instillation.


Results: The rate of tumor implantation was 90% of the animals submitted to tumor inoculation. We obtained reduction of the average weights of bladder in groups BCG and rBCG-S1PT ((p<0.001). In both groups treated with immunotherapy, there was an increase of expression of interleukins related to Th1, which was more intense in the group treated with rBCG-S1PT (p<0.05). The analysis of survival showed a significant increase in the group of animals treated with rBCG-S1PT. The instillation of immunotherapeutic agents in animals without tumor did not demonstrate histological differences when compared to the control group.


Conclusions: The establishment of the syngeneic orthotopic animal model was successful. The immunotherapy with rBCG-S1PT demonstrated more benefits than BCG in the treatment of bladder cancer in mice, reducing the bladder weight and increasing survival. The immune response obtained with the rBCG-S1PT expressed higher cytokines related to Th1. This new recombinant agent may promote better bladder tumor control than BCG imunotherapy in a clinical setting.