Combination bacteriolytic therapy for the treatment of experimental tumors

Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer.

[1]  R. C. Parker,et al.  Effect of Histolyticus Infection and Toxin on Transplantable Mouse Tumors.∗ , 1947, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[2]  R. A. Malmgren,et al.  Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. , 1955, Cancer research.

[3]  D. Gericke,et al.  ONCOLYSIS BY CLOSTRIDIA. II. EXPERIMENTS ON A TUMOR SPECTRUM WITH A VARIETY OF CLOSTRIDIA IN COMBINATION WITH HEAVY METAL. , 1964, Cancer research.

[4]  J. Moese,et al.  ONCOLYSIS BY CLOSTRIDIA. I. ACTIVITY OF CLOSTRIDIUM BUTYRICUM (M-55) AND OTHER NONPATHOGENIC CLOSTRIDIA AGAINST THE EHRLICH CARCINOMA. , 1964, Cancer research.

[5]  G. E. Boxer,et al.  ONCOLYSIS BY CLOSTRIDIA. III. EFFECTS OF CLOSTRIDIA AND CHEMOTHERAPEUTIC AGENTS ON RODENT TUMORS. , 1964, Cancer research.

[6]  E. Neter,et al.  Clostridial oncolysis in man , 1967 .

[7]  N. A. Boyd,et al.  The prevention of experimental Clostridium novyi gas gangrene in high-velocity missile wounds by passive immunisation. , 1972, Journal of medical microbiology.

[8]  N. A. Boyd,et al.  The prevention of experimental Clostridium novyi and Cl. perfringens gas gangrene in high-velocity missile wounds by active immunisation. , 1972, Journal of medical microbiology.

[9]  H. O. Bagadi,et al.  Experimental studies on infectious necrotic hepatitis (Black Disease) of sheep. , 1973, Research in veterinary science.

[10]  J. A. Meyers,et al.  Interspecies Conversion of Clostridium botulinum Type C to Clostridium novyi Type A by Bacteriophage , 1974, Science.

[11]  J. A. Meyers,et al.  Relationship of bacteriophages to alpha toxin production in Clostridium novyi types A and B , 1976, Infection and immunity.

[12]  Y. Kohwi,et al.  Antitumor effect of Bifidobacterium infantis in mice. , 1978, Gan.

[13]  S. Taniguchi,et al.  Selective localization and growth of Bifidobacterium bifidum in mouse tumors following intravenous administration. , 1980, Cancer research.

[14]  A. Mason,et al.  Experimental Proteus mirabilis burn surface infection. , 1982, Archives of surgery.

[15]  S. Cole,et al.  Molecular genetics and pathogenesis of Clostridium perfringens , 1991, Microbiological reviews.

[16]  C. von Eichel-Streiber,et al.  A comparative biochemical, pharmacological and immunological study of Clostridium novyi alpha-toxin, C. difficile toxin B and C. sordellii lethal toxin. , 1991, Toxicon : official journal of the International Society on Toxinology.

[17]  T. Wilkins,et al.  Comparison of Clostridium sordellii toxins HT and LT with toxins A and B of C. difficile. , 1992, Journal of medical microbiology.

[18]  S. Nakamura,et al.  Phylogenetic analysis of phospholipase C genes from Clostridium perfringens types A to E and Clostridium novyi , 1995, Journal of bacteriology.

[19]  A. Giaccia,et al.  Anaerobic bacteria as a delivery system for cancer gene therapy: in vitro activation of 5-fluorocytosine by genetically engineered clostridia. , 1996, Gene therapy.

[20]  P. V. Zijl,et al.  Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment , 1997, Gene Therapy.

[21]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[22]  C. Springer,et al.  Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent. , 1999, Cancer research.

[23]  Samuel I. Miller,et al.  Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo , 1999, Nature Biotechnology.

[24]  C. Lee,et al.  Clostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens. , 2000, The Journal of infectious diseases.

[25]  M. Sznol,et al.  Use of preferentially replicating bacteria for the treatment of cancer. , 2000, The Journal of clinical investigation.

[26]  X. Luo,et al.  Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. , 2000, The Journal of infectious diseases.

[27]  Y. Kano,et al.  Bifidobacterium longum as a delivery system for cancer gene therapy: Selective localization and growth in hypoxic tumors , 2000, Cancer Gene Therapy.

[28]  R. Pedley,et al.  Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin a-4 3-O-phosphate. , 2001, Cancer research.

[29]  R. Jain.  Delivery of molecular and cellular medicine to solid tumors. , 2001, Advanced drug delivery reviews.

[30]  A. Altman.  Acute tumor lysis syndrome. , 2001, Seminars in oncology.

[31]  G. Sledge,et al.  The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. , 2001, Cancer research.

[32]  P. Lambin,et al.  Improvement of Clostridium tumour targeting vectors evaluated in rat rhabdomyosarcomas. , 2001, FEMS immunology and medical microbiology.