The Journal of urology · 2004
Immunotherapy for bladder cancer using recombinant bacillus Calmette-Guerin DNA vaccines and interleukin-12 DNA vaccine.
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Lee Chi-Feng, Chang Suh-Yran, Hsieh Dar-Shih, Yu Dah-Shyong
Аннотация
PURPOSE: We investigated the efficacy of recombinant bacillus Calmette-Guerin (BCG) DNA (poly-rBCG) and murine interleukin (IL)-12 (mIL-12) vaccines in inducing T helper 1 polarized cytokines and suppressing bladder tumor growth in mice.
MATERIALS AND METHODS: Four mycobacteria candidate genes (Ag85A, Ag85B, Mpt64 and PstS3) were cloned, fused with ESAT6 and ligated into eukaryotic expression vectors. Combined poly-rBCG and mIL-12 vaccines were transferred into a murine bladder tumor model. The efficiency of gene expression was detected using Western blotting, flow cytometry and semiquantitative reverse transcriptase-polymerase chain reaction. Systemic cytokine responses, tumor growth and cumulative survival rates were monitored.
RESULTS: Transfected bladder cancer cells showed high in vitro and in vivo expression of the recombinant subcomponents. Mice with tumors injected with poly-rBCG plus mIL-12 produced serum interferon-gamma significantly within 21 days but no significant elevations in tumor necrosis factor-alpha, IL-2, IL-4 or IL-5 were found. On day 28 after electroporation the growth of MBT-2 implants treated with poly-rBCG, mIL-12 or poly-rBCG plus mIL-12 was significantly inhibited. The cumulative survival of mice treated with poly-rBCG plus mIL-12 was significantly higher than that of the other 3 groups.
CONCLUSIONS: Highly immunopotent recombinant vaccines of bacillus Calmette-Guerin DNA were produced that elicited T helper 1 immune responses with a high serum interferon-gamma level, inhibited tumor growth and prolonged the survival of tumor bearing mice. Thus, electroporation immunogene therapy using poly-rBCG plus mIL-12 may be an attractive regimen for the treatment of bladder cancer.
MATERIALS AND METHODS: Four mycobacteria candidate genes (Ag85A, Ag85B, Mpt64 and PstS3) were cloned, fused with ESAT6 and ligated into eukaryotic expression vectors. Combined poly-rBCG and mIL-12 vaccines were transferred into a murine bladder tumor model. The efficiency of gene expression was detected using Western blotting, flow cytometry and semiquantitative reverse transcriptase-polymerase chain reaction. Systemic cytokine responses, tumor growth and cumulative survival rates were monitored.
RESULTS: Transfected bladder cancer cells showed high in vitro and in vivo expression of the recombinant subcomponents. Mice with tumors injected with poly-rBCG plus mIL-12 produced serum interferon-gamma significantly within 21 days but no significant elevations in tumor necrosis factor-alpha, IL-2, IL-4 or IL-5 were found. On day 28 after electroporation the growth of MBT-2 implants treated with poly-rBCG, mIL-12 or poly-rBCG plus mIL-12 was significantly inhibited. The cumulative survival of mice treated with poly-rBCG plus mIL-12 was significantly higher than that of the other 3 groups.
CONCLUSIONS: Highly immunopotent recombinant vaccines of bacillus Calmette-Guerin DNA were produced that elicited T helper 1 immune responses with a high serum interferon-gamma level, inhibited tumor growth and prolonged the survival of tumor bearing mice. Thus, electroporation immunogene therapy using poly-rBCG plus mIL-12 may be an attractive regimen for the treatment of bladder cancer.