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,
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
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.