Tumor-Targeting Therapy Using Gene-Engineered Anaerobic-Nonpathogenic Bifidobacterium longum

  • Shun’ichiro TaniguchiEmail author
  • Yuko Shimatani
  • Minoru Fujimori
Part of the Methods in Molecular Biology book series (MIMB, volume 1409)


Despite great progress in molecular-targeting drugs for cancer treatment, there are problems of disease recurrence due to cancer-cell resistance to those drugs, derived from the heterogeneity of tumors. On one hand, the low-oxygen microenvironment present in malignant tumor tissues has been regarded as a source of resistance of cancer cells against conventional therapie, such as radiation and chemotherapy. To overcome these problems, we have been developing a system to selectively deliver a large amount of anticancer drugs to malignant tumors by making use of the limiting factor, hypoxia, in tumors. Our strategy is to use hypoxia as a selective target. Here, we show methods and protocols using the nonpathogenic obligate anaerobic Bifidobacterium longum as a drug-delivery system (DDS) to target anaerobic tumor tissue.

Key words

Tumor targeting Cancer therapy Anaerobic Oxygen Hypoxia Carrier DDS Nonpathogenic Bifidobacterium longum 



We thank all of our colleagues at Anaeropharma Science, Inc. for their technical support and useful discussions.


  1. 1.
    Kimura NT, Taniguchi S, Aoki K, Baba T (1980) Selective localization and growth of Bifidobacterium bifidom in mouse tumors following intraveneous administration. Cancer Res 40:2061–2068PubMedGoogle Scholar
  2. 2.
    Taniguchi S, Fujimori M, Sasaki T, Tsutsui H, Shimatani Y, Seki K, Amano J (2010) Targeting solid tumors with non-pathogenic obligate anaerobic bacteria. Cancer Sci 101:1925–1932CrossRefPubMedGoogle Scholar
  3. 3.
    Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425–437PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Sullivan R, Graham CH (2007) Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26:319–331CrossRefPubMedGoogle Scholar
  5. 5.
    Yazawa K, Fujimori M, Nakamura T, Sasaki T, Amano J, Kano Y, Taniguchi S (2001) Bifidobacterium longum as a delivery system for gene therapy of chemically induced rat mammary tumors. Breast Cancer Res Treat 66:165–170CrossRefPubMedGoogle Scholar
  6. 6.
    Nakamura T, Sasaki T, Fujimori M, Yazawa K, Kano Y, Amano J, Taniguchi S (2002) Cloned cytosine deaminase gene expression of Bifidobacterium longum and application to enzyme/ pro-drug therapy of hypoxic solid tumors. Biosci Biotechnol Biochem 66:2362–2366CrossRefPubMedGoogle Scholar
  7. 7.
    Yazawa K, Fujimori M, Amano J, Kano Y, Taniguchi S (2000) Bifidobacterium longum as a delivery system for cancer gene therapy: selective localization and growth in hypoxic tumors. Cancer Gene Ther 7:269–274CrossRefPubMedGoogle Scholar
  8. 8.
    Sasaki T, Fujimori M, Hamaji Y, Hama Y, Ito K, Amano J, Taniguchi S (2006) Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. Cancer Sci 97:649–657CrossRefPubMedGoogle Scholar
  9. 9.
    Forbes NS (2010) Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10:785–794PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Gueniche A, Knaudt B, Schuck E, Volz T, Bastien P et al (2008) Effects of nonpathogenic gramnegative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: a prospective, randomized, double-blind, placebo-controlled clinical study. Br J Dermatol 159:1357–1363CrossRefPubMedGoogle Scholar
  11. 11.
    He X, Lux R, Kuramitsu HK, Anderson MH, Shi W (2009) Achieving probiotic effects via modulating oral microbial ecology. Adv Dent Res 21:53–56PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ et al (2002) Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20:142–152PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Wei MQ, Mengesha A, Good D, Anne J (2008) Bacterial targeted tumour therapy dawn of a new era. Cancer Lett 259:16–27CrossRefPubMedGoogle Scholar
  14. 14.
    Takeuchi A, Matsumura H, Kano Y (2002) Cloning and expression in Escherichia coli of a gene, hup, encoding the histone-like protein HU of Bifidobacterium longum. Biosci Biotechnol Biochem 66:598–603CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Shun’ichiro Taniguchi
    • 1
    • 2
    Email author
  • Yuko Shimatani
    • 2
  • Minoru Fujimori
    • 2
    • 3
  1. 1.Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge ResearchShinshu University Graduate School of MedicineMatsumotoJapan
  2. 2.Anaeropharma Science, Inc.MatsumotoJapan
  3. 3.Tokyo Medical University, Ibaraki Medical CenterIbarakiJapan

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