Using of genetically modified strains of Salmonella typhimurium as Cancer Therapy
Strains of Salmonella typhimurium and other bacteria tend to target tumors and have been used for cancer therapy and as vehicles of gene delivery in enzyme prodrug therapy (1). In previous Gene-Directed
Enzyme Prodrug Therapy (GDEPT) work with a number of reductive prodrugs, including 6-chloro-9-nitro-5-
oxo-5H-benzo [a] phenoxazine (CNOB), it employed S. typhimurium strain SL7838 (sopE and aroA) to deliver the chrR6 gene to tumors. SL7838 is attenuated with enhanced preference for tumor localization, and the chrR6- encoded enzyme (ChrR6) possesses superior capacity to activate reductive prodrugs (2,3). There
are previous studies used other an attenuated strains of S. typhimurium with other cancer prodrugs like CB1954 and 5-fluorocytosine, and success has been observed in vivo, and both are currently undergoing
phase I clinical trials in cancer patients (4). This strategy overcomes the unacceptable side effects of bacterial therapy and uses anaerobic or facultative anaerobic bacteria that have been transformed with an enzyme that can convert a non-toxic prodrug into a toxic drug. With the proliferation of the bacteria in the necrotic and
hypoxic areas of the tumor, the enzyme is expressed solely in the tumor. Thus a systemically applied prodrug is metabolized to the toxic drug only in the tumor.
Attenuated invasive S. typhimurium has been reported to infect malignant cells both in vitro and in vivo,
thereby triggering the immune response. Attenuated S. typhimurium has demonstrated successful invasion of melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-Salmonella-specific T cells. However, better outcomes were achieved after vaccinating tumor bearing mice
with S. typhimurium before intratumoral Salmonella injection (5). Genetically engineered attenuated strains of S. typhimurium expressing murine cytokines have exhibited the capacity to modulate immunity to infection and have retarded the growth of experimental melanomas. Results have suggested that IL-2 encoding Salmonella organisms are superior in suppressing tumor growth as compared to the parental noncytokine- expressing strain (6). A xenogenic DNA vaccine encoding human tumor endothelial marker 8
(TEM8) carried by attenuated S. typhimurium has been reported to generate TEM8-specific CD8 cytotoxic T-cell response after oral administration. Suppression of angiogenesis in the tumors alongwith protection of mice from lethal challenges against tumor cells and reduced tumor growth support the potential of
antiangiogenesis immunotherapy (7).
References:
1. Dang LH, Bettegowda C, Huso DL, Kinzler KW and Vogelstein B: Combination bacteriolytic therapy for
the treatment of experimental tumors. Proceedings of the National Academy of Sciences of the United States
of America 2001, 98(26):15155-15160.
2. Barak Y, Thorne SH, Ackerley DF, Lynch SV, Contag CH and Matin A: New enzyme for reductive
cancer chemotherapy, YieF, and its improvement by directed evolution. Mol Cancer Ther 2006, 5(1):97-103.
3. Thorne SH, Barak Y, Liang W, Bachmann MH, Rao J, Contag CH, Matin A: CNOB/ChrR6, a new
prodrug enzyme cancer chemotherapy. Mol Cancer Ther 2009, 8(2):333-341.
4. Luo X, Li Z, Shen SY, Runyan JD, Bermudes D and Zheng LM: Genetically armed Salmonella
typhimurium delivered therapeutic gene and inhibited tumor growth in preclinical models. Proc Annu Meet
Am Assoc Cancer Res 2001, 42:3693.
5. Avogadri F, Martinoli C, Petrovska L, Chiodoni C, Transidico P, Bronte V, Longhi R, Colombo MP,
Dougan G and Rescigno M: Cancer Immunotherapy Based on Killing of Salmonella-Infected Tumor Cells.
Cancer Res 2005, 65(9):3920-3927.
6. Al-Ramadi BK, Fernandez-Cabezudo MJ, El-Hasasna H, Al-Salam S, Attoub S, Xu D and Chouaib S:
Attenuated Bacteria as Effectors in Cancer Immunotherapy. Ann N Y Acad Sci 2008, 1138(1):351-357.
7. Ruan Z, Yang Z, Wang Y, Wang H, Chen Y, Shang X, Yang C, Guo S, Han J, Liang H and Wu Y: DNA
vaccine against tumor endothelial marker 8 inhibits tumor angiogenesis and growth. J Immunother 2009,32(5):486-491.
1. Dang LH, Bettegowda C, Huso DL, Kinzler KW and Vogelstein B: Combination bacteriolytic therapy for
the treatment of experimental tumors. Proceedings of the National Academy of Sciences of the United States
of America 2001, 98(26):15155-15160.
2. Barak Y, Thorne SH, Ackerley DF, Lynch SV, Contag CH and Matin A: New enzyme for reductive
cancer chemotherapy, YieF, and its improvement by directed evolution. Mol Cancer Ther 2006, 5(1):97-103.
3. Thorne SH, Barak Y, Liang W, Bachmann MH, Rao J, Contag CH, Matin A: CNOB/ChrR6, a new
prodrug enzyme cancer chemotherapy. Mol Cancer Ther 2009, 8(2):333-341.
4. Luo X, Li Z, Shen SY, Runyan JD, Bermudes D and Zheng LM: Genetically armed Salmonella
typhimurium delivered therapeutic gene and inhibited tumor growth in preclinical models. Proc Annu Meet
Am Assoc Cancer Res 2001, 42:3693.
5. Avogadri F, Martinoli C, Petrovska L, Chiodoni C, Transidico P, Bronte V, Longhi R, Colombo MP,
Dougan G and Rescigno M: Cancer Immunotherapy Based on Killing of Salmonella-Infected Tumor Cells.
Cancer Res 2005, 65(9):3920-3927.
6. Al-Ramadi BK, Fernandez-Cabezudo MJ, El-Hasasna H, Al-Salam S, Attoub S, Xu D and Chouaib S:
Attenuated Bacteria as Effectors in Cancer Immunotherapy. Ann N Y Acad Sci 2008, 1138(1):351-357.
7. Ruan Z, Yang Z, Wang Y, Wang H, Chen Y, Shang X, Yang C, Guo S, Han J, Liang H and Wu Y: DNA
vaccine against tumor endothelial marker 8 inhibits tumor angiogenesis and growth. J Immunother 2009,32(5):486-491.
By: Fairoz A. N. Al- Wrafy
Polish Academy of Sciences , Institute of Immunology and Experimental Therapy
Wroclaw, Poland
*Graduated of TAiz university - science college -Microbiology department
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