Improvement of bladder cancer immunotherapy by creating a recombinant Bacille Calmette-Gu'erin which secrets p53 protein

BCG Department, Research and Production Complex, Pasteur Institute of Iran, Tehran 31599, Iran.
Medical Hypotheses (Impact Factor: 1.07). 07/2009; 72(6):754. DOI: 10.1016/j.mehy.2009.01.035
Source: PubMed
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    • "Intensive research has been carried out to find less toxic and more potent therapeutic agents for the immunotherapy of bladder tumors (Yuksel et al. 2011). The development of immunotherapy based on recombinant BCG (rBCG) overexpressing antigens or expressing foreign antigens is a promising approach to improve the performance of BCG anti-tumour therapy (Amirkhah et al. 2009) and current studies are developing rBCG strains to further improve the effectiveness of the therapy (Andrade et al. 2010; Ding et al. 2012; Lee et al. 2004; Luo et al. 2004; Yu et al. 2004). The Ag85 complex, comprising of Ag85A, Ag85B and Ag85C proteins, includes the major protective antigens shared by both BCG and M. tuberculosis (Wiker and Harboe 1992). "
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    ABSTRACT: BCG therapy remains at the forefront of immunotherapy for treating patients with superficial bladder cancer. The high incidence of local side effects and the presence of non-responder diseases have led to efforts to improve the therapy. Hence, we proposed that an auxotrophic recombinant BCG strain overexpressing Ag85B (BCG ∆leuD/Ag85B), could enhance the cytotoxicity to the human bladder carcinoma cell line 5637. The rBCG was generated using an expression plasmid encoding the mycobacterial antigen Ag85B to transform a BCG ∆leuD strain. The inhibitory effect of BCG ∆leuD/Ag85B on 5637 cells was determined by the MTT method, morphology observation and a LIVE/DEAD assay. Gene expression profiles for apoptotic, cell cycle-related and oxidative stress-related genes were investigated by qRT-PCR. Bax, bcl-2 and p53 induction by BCG ∆leuD/Ag85B treatment was evaluated by Western blotting. BCG ∆leuD/Ag85B revealed a superior cytotoxicity effect compared to the control strains used in this study. The results showed that the expression level of pro-apoptotic and cell cycle-related genes increased after BCG ∆leuD/Ag85B treatment, whereas the mRNA levels of anti-apoptotic genes decreased. Interestingly, BCG ∆leuD/Ag85B also increased the mRNA level of antioxidant enzymes in the bladder cancer cell line. Bax and p53 proteins levels increased following treatment. In conclusion, these results suggest that treatment with BCG ∆leuD/Ag85B enhances cytotoxicity for superficial bladder cancer cells in vitro. Therefore, rBCG therapy may have potential benefits in the treatment of bladder cancer.
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