Clostridium as a Cancer Therapy
Clostridium is one of the largest prokaryotic genera and consists of a diverse range of obligatory anaerobic bacteria. Most of these bacteria are flagellated and motile. These bacteria are Gram-positive and rod-shaped, and capable of forming endospores. Clostridium bacteria can undergo a complex cell differentiation process that produces endospores that are highly resistant to harsh environmental conditions and can withstand high temperature, disinfectants, and low-energy radiation. The genus includes common free-living bacteria and pathogens. Several pathogens producing potent toxins are part of this genera including C. tetani, C. botulinum, C. difficile, and C. perfringens. C. tetani and C. botulinum are both well-studied species linked to human diseases and are potent bacterial toxins. C. tetani is the causative agent of tetanus, and Clostridium botulinum is related to food poisoning and causes botulism. Other members of the Clostridium genus include Clostridium perfringens which can infect wounds and cause gas gangrene, and Clostridium difficile, which grows in the gut during antibiotic therapy to cause pseudomembranous enterocolitis. Recently, Clostridium novyi type A has been associated with an outbreak of serious illness and death amongst intravenous drug users. However, most Clostridium species are nonpathogenic. Many are harmless and can be found in the soil. Some species have applications in bioremediation and wastewater treatment. Nonpathogenic species include the industrially valuable Clostridium acetobutylicum and Clostridium beijerinckii. These solventogenic clostridia are used in acetone, butanol and isopropanol fermentation.
Anticancer Properties
Clostridium’s anaerobic nature and ability to form resistive spores make it an ideal candidate for cancer therapy and anticancer treatment. Recently, advances have been made in cancer therapy and treatment using Clostridium bacteria. Although conventional anticancer therapies such as surgical resection, radiotherapy, and chemotherapy have proven effective, alternative techniques are being developed to increase efficiency against a wider range of cancer cases, to increase specificity of such therapies, to improve current techniques, and to minimize side effects. Experimental cancer treatments are medical therapies intended to treat cancer by improving, supplementing or replacing current conventional methods. A proposed option for treatment of avascular or hypoxic regions of tumors has been the use of anaerobic bacteria such as Clostridium. Some clostridia show innate oncolytic activity based on their specificity to germinate in the hypoxic and necrotic regions of solid tumors. Clostridium spores are selective and can only germinate within the hypoxic and necrotic regions of the tumors. Combined with their ability to produce spores, intravenous administration of spores from nonpathogenic strains of Clostridia will lead to spores that only germinate in the hypoxic areas of solid cancer tumors. As a result, this specificity can be used to target cancerous tumors marked by uncontrolled growth and low oxygen levels that can provide a niche for anaerobic bacteria such as Clostridium. With Clostridium-directed tumor therapy, advantages include tumor selectivity and safety of using nonpathogenic clostridia in cancer treatment.
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Historical Uses
Applying clostridia for cancer treatment originated nearly 80 years ago.
Traditional Cancer Treatment
Traditional cancer therapies involve regulating of cell division and growth most commonly at the genetic level. Conventional methods involve delivering tumor suppressor genes to cancer cells, delivering genes that activate toxic products that kills tumor cells and their neighbors, introducing defective genes that cause cell death, and directly attacking tumor cells and harnessing the immune responses to tumor antigens. However, the primary problem with such traditional methods is the lack of tumor specificity. Disadvantages of both viral and non-viral gene delivery methods include but are not limited to low transfection transduction levels, immune responses that my hinder repeated administrations of the vector, potential random integrations from retroviruses that could have carcinogenic effects, and a preferential infection of nondividing cells. Most drugs and current treatments are effective against rapidly dividing tumor cells but not against hypoxic regions in which cell proliferation is decreased. As a result, hypoxia in tumor tissues can be exploited for tumor specific therapies using bacteria based therapies. Anaerobic bacteria can specifically colonize the hypoxic or necrotic regions or the tumors and either directly exert innate oncolytic effects or act as a vector in brining locally expressed therapeutic proteins.
Bacteria-directed cancer treatment has advantages over the traditional cancer therapies. Some nonrecombinant bacteria already exert inherent antitumor activities, and recombinant bacteria can be used as vectors to producing protein of therapeutic interest in tumor environments as an alternative to gene therapy. Through the bacterial-directed protein delivery system, there will be an efficient distribution of vector throughout the tumor mass with sufficient transfection levels and transient gene expression. This method prevents the random insertion of foreign DNA into the genome and the transfection of tumor cells with therapeutic genes that may instead enhance antitumor properties. The bacteria can then be inactivated at any moment during therapy by administering antibiotics.
Other bacterial treatments
Other anerobic bacterial species including Bifodobacterium, Streptococcus pyogenes, and Salmonella Typhimurium are under investigation. Streptococcus pyogenes and Salmonella typhimurium have been used with some success in clinical trials.
Further Reading
References
Connell, H. C. (1935). The study and treatment of cancer by proteolytic enzymes: preliminary report. Canadian Medical Association journal, 33(4), 364. Malmgren, R. A., & Flanigan, C. C. (1955). Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer research, 15(7), 473-478. Thiele, E. H., Arison, R. N., & Boxer, G. E. (1964). Oncolysis by clostridia. III. Effects of clostridia and chemotherapeutic agents on rodent tumors. Cancer research, 24(2 Part 1), 222-233. Lemmon, M. J., Van Zijl, P., Fox, M. E., Mauchline, M. L., Giaccia, A. J., Minton, N. P., & Brown, J. M. (1997). Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene therapy, 4(8), 791-796. Liu, S. C., Minton, N. P., Giaccia, A. J., & Brown, J. M. (2002). Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene therapy, 9(4), 291-296. Minton, N. P. (2003). Clostridia in cancer therapy. Nature Reviews Microbiology, 1(3), 237-242. Dang, L. H., Bettegowda, C., Huso, D. L., Kinzler, K. W., & Vogelstein, B. (2001). Combination bacteriolytic therapy for the treatment of experimental tumors. Proceedings of the National Academy of Sciences, 98(26), 15155-15160. Barbé, S., Van Mellaert, L., & Anné, J. (2006). The use of clostridial spores for cancer treatment. Journal of applied microbiology, 101(3), 571-578.
Edited by Anh Tran, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.
