Abstract
A major obstacle in cancer gene therapy is selective tumor delivery. Previous studies have suggested that genetically engineered anaerobes of the genus Clostridium might be gene therapy vectors because of their ability to proliferate selectively in the hypoxic/necrotic regions common to solid tumors. However, the tumor colonization efficiency of the strain previously used was insufficient to produce any antitumor effect. Here we describe for the first time the successful transformation of C. sporogenes, a clostridial strain with the highest reported tumor colonization efficiency, with the E. coli cytosine deaminase (CD) gene and show that systemically injected spores of these bacteria express CD only in the tumor. This enzyme can convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU). Furthermore, systemic delivery of 5-FC into mice previously injected with CD-transformed spores of C. sporogenes produced greater antitumor effect than maximally tolerated doses of 5-FU. Since most human solid tumors have hypoxic and necrotic areas this vector system has considerable promise for tumor-selective gene therapy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Minton N.P. et al. Chemotherapeutic tumour targeting using clostridial spores FEMS Microbiol Rev 1995 17: 357 357
Fox M.E. et al. Anaerobic bacteria as a delivery system for cancer gene therapy: activation of 5-fluorocytosine by genetically engineered clostridia Gene Therapy 1996 3: 173 173
Lemmon M.L. et al. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment Gene Therapy 1997 4: 791 791
Malmgren R.A., Flanigan C.C. . Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration Cancer Res 1955 15: 473 473
Möse J.R., Möse G. . Onkolyseversuche mit apathogenen anaeroben Sporenbildern am Ehrlich Tumor des Maus Z Krebsforsch 1959 63: 63 63
Möse J.R., Möse G. . Oncolysis by clostridia. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic clostridia against the Ehrlich carcinoma Cancer Res 1964 24: 212 212
Thiele E.H., Arison R.N., Boxer G.E. . Oncolysis by clostridia. III. Effects of clostridia and chemotherapeutic agents on rodent tumors Cancer Res 1964 2: 222 222
Engelbart K., Gericke D. . Oncolysis by clostridia V. Transplanted tumors of the hamster Cancer Res 1954 24: 239 239
Carey R.W. et al. Clostridial oncolysis in man Eur J Cancer 1967 3: 37 37
Heppner F., Mose J.R. . The liquefaction (oncolysis) of malignant gliomas by a non-pathogenic clostridium Acta Neurol 1978 12: 123 123
Heppner F., Mose J., Ascher P.W., Walter G. . Oncolysis of malignant gliomas of the brain 13th Int Cong Chemother 1983 226: 38 38
Kievit E. et al. Superiority of yeast over bacterial cytosine deaminase for enzyme/prodrug gene therapy in colon cancer xenografts Cancer Res 1999 59: 1417 1417
Lawrence T.S. et al. Preferential cytotoxicity of cells transduced with cytosine deaminase compared to bystander cells after treatment with 5-flucytosine Cancer Res 1998 58: 2588 2588
Krasnykh V. et al. Advanced generation adenoviral vectors possess augmented gene transfer efficiency based upon coxsackie adenovirus receptor-independent cellular entry capacity Cancer Res 2000 60: 6784 6784
Xu L. et al. Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts Hum Gene Ther 1999 10: 2941 2941
Pawelek J.M., Low K.B., Bermudes D. . Tumor-targeted Salmonella as a novel anticancer vector Cancer Res 1997 57: 4537 4537
Low K.B. et al. Lipid A mutant Salmonella with suppressed virulence and TNFalpha induction retain tumor-targeting in vivo Nat Biotechnol 1999 17: 37 37
Fabricius E.M. et al. Quantitative investigations into the elimination of in vitro-obtained spores of the non-pathogenic Clostridium butyricum strain CNRZ 528, and their persistence in organs of different species following intravenous spore administration Res Microbiol 1993 144: 741 741
Gericke D. et al. Further progress with oncolysis due to apathogenic clostridia Zentralbl Bakteriol 1979 243: 102 102
Streilein J.W. . Unraveling immune privilege Science 1995 270: 1158 1158
Hirst D.G., Brown J.M., Hazlehurst J.L. . Enhancement of CCNU cytotoxicity by misonidazole: possible therapeutic gain Br J Cancer 1982 46: 109 109
Minton N.P. et al. Clostridial cloning vectors Woods DR (eds); The Clostridia and Biotechnology Butterworth-Heinemann 1993 pp 119–150
Oultram J.D. et al. Introduction of plasmids into whole cells of Clostridium acetobutylicum by electroporation FEMS Microbiol Letts 1988 56: 83 83
Acknowledgements
This work was supported by USPHS grant CA 64697 awarded to JMB from the US National Cancer Institute and funds to NPM from the UK Department of Health.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Liu, SC., Minton, N., Giaccia, A. et al. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9, 291–296 (2002). https://doi.org/10.1038/sj.gt.3301659
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301659
Keywords
This article is cited by
-
Clostridium Bacteria: Harnessing Tumour Necrosis for Targeted Gene Delivery
Molecular Diagnosis & Therapy (2024)
-
Bacteria-driven hypoxia targeting delivery of chemotherapeutic drug proving outcome of breast cancer
Journal of Nanobiotechnology (2022)
-
Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours
Cancer Gene Therapy (2022)
-
Engineering the gut microbiota to treat chronic diseases
Applied Microbiology and Biotechnology (2020)
-
Building sophisticated sensors of extracellular cues that enable mammalian cells to work as “doctors” in the body
Cellular and Molecular Life Sciences (2020)