Advertisement

Breast Cancer

, 13:27 | Cite as

Genetically engineeredbifidobacterium as a drug delivery system for systemic therapy of metastatic breast cancer patients

  • Minoru FujimoriEmail author
Review Article

Abstract

A fundamental obstacle in systemic therapy for metastatic breast cancer patients is specific targeting of therapy directly to a solid tumor. Hypoxic or necrotic regions are characteristic of solid tumors in many murine and human tumors, including the majority of primary tumors of the breast. A strain of anaerobic bacteria such asBifidobacterium orClostridium selectively localizes to and proliferates in solid tumors after systemic application. Another approach uses attenuatedSalmonella strains that need tumor-specific nutrients to selectively proliferate and is a potential gene delivery system. We constructed a plasmid, pBLESl00-S-eCD, which included the cytosine deaminase gene. TransfectedBifidobacterium longum produced cytosine deaminase in the hypoxic tumor. Enzyme/pro-drug therapy was confirmed to be effective for systemic administration.

Key words

Genetically engineered bacteria Tumor targeting Hypoxia 

References

  1. 1).
    Moulder JE, Rockwell S: Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and survey of existing data.Int J Radiat Oncol Biol Phys 10:695–712, 1984.PubMedGoogle Scholar
  2. 2).
    Vaupel PW, Hockel M: Oxygenation status of human tumors: a reappraisal using computerized pO2 histography. In: Vaupel PW, Kelleher DK, Gunderoth M (eds) Tumor Oxygenation. Fischer-Verlag, New York, Stuttgart, pp219–232, 1994.Google Scholar
  3. 3).
    Hockel M, Schlenger K, Knoop C, Vaupel PW: Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements.Cancer Res 51:6098–6102, 1991.PubMedGoogle Scholar
  4. 4).
    Vaupel PW: Oxygeneration of solid tumors. In Teicher BA, ed: Drug Resistance in Oncology. Marcel Dekker, New York, pp53–85, 1993.Google Scholar
  5. 5).
    Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KMS, Stratford IJ, Harris AL: Targeting gene expression to hypoxic tumor cells.Nat Med 3515–520, 1997.PubMedCrossRefGoogle Scholar
  6. 6).
    Malmgren RA, Flanigan CC: Localization of the vegetative from of Clostridium tetani in mouse tumors following intravenous spore administration.Cancer Res 15:473–478, 1955.PubMedGoogle Scholar
  7. 7).
    Kimura NT, Taniguchi S, Aoki K: Selective localization and growth of Bifidobacterium bifidum in mouse tumors following intravenous administration.Cancer Res 40:2061–2068, 1980.PubMedGoogle Scholar
  8. 8).
    Argnani A, Leer RJ, van Luijk N, Pouwels PH: A convenient and reproducible method to genetically transform bacteria of the genus Bifidobacterium.Microbiology 142:109–114, 1996.PubMedGoogle Scholar
  9. 9).
    Matsumura H, Takeuchi A, Kano Y: Construction of Escherichia coli-Bifidobacterium longum shuttle vector transforming B. longum 105-A and 108-A.Biosci Biotech Biochem 61:1211–1212, 1997.CrossRefGoogle Scholar
  10. 10).
    Yazawa K, Fujimori M, Amano J, Kano Y, Taniguchi S: Bifidobacterium longum as a delivery system for cancer gene therapy: selective localization and growth in hypoxic tumors.Cancer Gene Ther 7:269–274, 2000.PubMedCrossRefGoogle Scholar
  11. 11).
    Yazawa K, Fujimori M, Nakamura T, Sasaki T, Amano J, Kano Y, Taniguchi S: Bifidobacterium longum as a delivery system for gene therapy of chemically induced rat mammary tumors.Breast Cancer Res Treat 66:165–170, 2001.PubMedCrossRefGoogle Scholar
  12. 12).
    Archer FL, Orlando RA: Morphology, natural history and enzyme patterns in mammary tumors of the rat induced by 7, 12-dimethylbenzanthrancene.Cancer Res 28:217–224, 1968.PubMedGoogle Scholar
  13. 13).
    Shimkin MB, Gruenstein M, Meranze DR, Acuff M, Thatcher D: The effect of schedule and dose of 7,12-dimethylbenzanthrancene on the induction and growth of mammary carcinomas in Sprague-Dawley rats.Cancer Res 29:503–505, 1969.PubMedGoogle Scholar
  14. 14).
    Takeuchi A, Matsumura H, Kano Y: Cloning and expression in escherichia coli of a gene, hup, encoding the histone-like protein HU of Bifidobacterium longum.Biosci Biotechnol Biochem 66:598–603, 2002.PubMedCrossRefGoogle Scholar
  15. 15).
    Nakamura T, Sasaki T, Fujimori M, Yazawa K, Kano Y, Amano J, Taniguchi S: Cloned cytosine deaminase gene expression of Bifidobacterium longum and application to enzyme/pro-drug therapy of hypoxic solid tumors.Biosci Biotech Biochem 66:2362–2366, 2002.CrossRefGoogle Scholar
  16. 16).
    Minton NP, Mauchline ML, Lemmon MJ, Brehm JK, Fox M, Michael NP, Giaccia A, Brown JM: Chemo-therapeutic tumor targeting using clostridial spores.FEMS Microbiol Rev 17:357–364, 1995.PubMedCrossRefGoogle Scholar
  17. 17).
    Fox ME, Lemmon MJ, Mauchline ML, Davis TO, Giaccia AJ, Minton NP, Brown JM: Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered Clostridia.Gene Ther 3:173–178, 1996.PubMedGoogle Scholar
  18. 18).
    Pawelek JM, Low KB, Bermudes D: Tumor-targeted Salmonella as a Novel Anticancer Vector.Cancer Res 57:4537–4544, 1997.PubMedGoogle Scholar
  19. 19).
    Theys J, Landuyt W, Nuyts S, Van Mellaert L, van Oosterom A, Lambin P, Anne J: Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum.Cancer Gene Ther 8:294–297, 2001.PubMedCrossRefGoogle Scholar
  20. 20).
    Mei S, Theys J, Landuyt W, Anne J, Lambin P: Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella Typhimurium.Anticancer Res 22:3261–3266, 2002.PubMedGoogle Scholar
  21. 21).
    Fox ME, Lemmon MJ, Mauchline ML, Davis TO, Giaccia AJ, Minton NP, Brown JM: Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered Clostridia.Gene Ther 3:173–178, 1996.PubMedGoogle Scholar
  22. 22).
    Carey RW, Holland JF, Whang HYet al: Clostridial oncolysis in man.Eur J Cancer 3:37–46, 1967.Google Scholar
  23. 23).
    Hone DM, Tacket CO, Harris AMet al: Evaluation in volunteers of a candidate live oral attenuated Salmonella typhy vector vaccine.J Clin Invest 90:412–420, 1992.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2006

Authors and Affiliations

  1. 1.Department of SurgeryShinshu University School of MedicineMatsumotoJapan

Personalised recommendations