Clostridium as a Cancer Therapy: Difference between revisions
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==Cancer Treatments== | ==Cancer Treatments== | ||
<b>Traditional cancer therapies <br></b> | |||
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. | 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. Hypoxia is a major cause of resistance to ionizing radiation and the dose required to kill hypoxic cells is up to 3 times higher compared with the same amount of well-oxygenated cells. Difficulties in delivering anticancer chemotherapeutics to the poorly vascularized, hypoxic regions of tumors can be overcome with bacteria-based tumor specific therapies using anaerobic bacteria. Anaerobic bacteria can specifically target 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. | Most drugs and current treatments are effective against rapidly dividing tumor cells but not against hypoxic regions in which cell proliferation is decreased. Hypoxia is a major cause of resistance to ionizing radiation and the dose required to kill hypoxic cells is up to 3 times higher compared with the same amount of well-oxygenated cells. Difficulties in delivering anticancer chemotherapeutics to the poorly vascularized, hypoxic regions of tumors can be overcome with bacteria-based tumor specific therapies using anaerobic bacteria. Anaerobic bacteria can specifically target 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. | <b>Bacteria-directed cancer therapies <br></b>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. | ||
==Research and Studies== | ==Research and Studies== | ||
Revision as of 06:15, 24 March 2015
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. Hypoxia is a major cause of resistance to ionizing radiation and the dose required to kill hypoxic cells is up to 3 times higher compared with the same amount of well-oxygenated cells. 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.
Clostridium novyi is a highly mobile spore-forming organism that is extremely sensitive to oxygen. Injection of C novyi takes advantage of the hypoxic and often necrotic nature of fast-growing tumors to serve as a selective tumor killer.
Cancer Treatments
Traditional cancer therapies
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. Hypoxia is a major cause of resistance to ionizing radiation and the dose required to kill hypoxic cells is up to 3 times higher compared with the same amount of well-oxygenated cells. Difficulties in delivering anticancer chemotherapeutics to the poorly vascularized, hypoxic regions of tumors can be overcome with bacteria-based tumor specific therapies using anaerobic bacteria. Anaerobic bacteria can specifically target 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 therapies
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.
Research and Studies
Previous attempts to treat advanced cancers using sterile filtrates of C. histolyticum produced proteolytic enzymes that degraded cancerous tissues without affecting normal tissue. Spores germinated in tumors after inoculation of C. histolyticum spores into mice with transplanted sarcomas and observed lysis of tumor tissues. Intravenously injected spores of nonpathogenic strains of Clostridium species in rodent tumor models with transplanted tumors resulted in softening of tumors and tumor cell death primarily in the tumor center. However, tumor regrowth occurred overtime from the remaining outer rim of viable cells. To specifically attack the remaining cancer cells at the tumor periphery, combination therapies have been studied to improve the therapeutic outcomes.
C. sporogenes was transformed with the E. coli codA gene encoding cytosine deaminase. When spores of this recombinant strain were administered to mice bearing SCCVII tumors followed by 5-fluorocytosine injection, a significant antitumor effect was observed. C. sporogenes was also engineered to produce nitroreductase by combining it with the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid administered 4 h after injection of spores. These recombinants showed a fourfold increase in tumor colonization and in combination with the respective prodrugs, complete tumor reduction was observed.
Administration of C. novyi-NT spores to nude mice with various human xenografts worked in combination with different amounts of radiotherapy. The best result was observed with brachytherapy, as a single dose of spores combined with this treatment resulted in 100% cure in mice. When immunocompetent tumor-bearing mice were treated with C. novyi-NT spores alone, only 30% of the animals exhibited complete tumor regression.
Clostridia is still currently under investigation for cancer therapy uses in humans. Recently, Clostridium species have been engineered to produce proteins of interest in antitumor therapy. Although Clostridia is not yet completely efficient to sufficiently control tumor growth, recent combination treatments have improved in preclinical antitumor responses. Combination of clostridial spores administration and vascular targeting agents increase tumor colonization and concentrations of degradative enzymes and therapeutic proteins in the tumor and also reduce the probability of incomplete tumor cell death or tumor regrowth. Ongoing studies are searching for the best combinations or recombinant cancer therapies using a bacterial approach.
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.
References
1. Barbé, S., Van Mellaert, L., & Anné, J. (2006). The use of clostridial spores for cancer treatment. Journal of applied microbiology, 101(3), 571-578.
2. Cheong, I., Huang, X., Bettegowda, C., Diaz, L. A., Kinzler, K. W., Zhou, S., & Vogelstein, B. (2006). A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science, 314(5803), 1308-1311.
3. Connell, H. C. (1935). The study and treatment of cancer by proteolytic enzymes: preliminary report. Canadian Medical Association journal, 33(4), 364.
4. 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.
5. 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.
6. 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.
7. 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.
8. Minton, N. P. (2003). Clostridia in cancer therapy. Nature Reviews Microbiology, 1(3), 237-242.
9. Patyar, S., Joshi, R., Byrav, D. S., Prakash, A., Medhi, B., & Das, B. K. (2010). Review Bacteria in cancer therapy: a novel experimental strategy. J Biomed Sci, 17(1), 21-30.
10. Pawelek, J. M., Low, K. B., & Bermudes, D. (2003). Bacteria as tumour-targeting vectors. The lancet oncology, 4(9), 548-556.
11. Plomp, M., McCaffery, J. M., Cheong, I., Huang, X., Bettegowda, C., Kinzler, K. W., ... & Malkin, A. J. (2007). Spore coat architecture of Clostridium novyi NT spores. Journal of bacteriology, 189(17), 6457-6468.
12. Ryan, R. M., Green, J., & Lewis, C. E. (2006). Use of bacteria in anti-cancer therapies. Bioessays, 28(1), 84-94.
13. 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.
14. Van Mellaert, L., Barbé, S., & Anné, J. (2006). Clostridium spores as anti-tumour agents. TRENDS in Microbiology, 14(4), 190
Edited by Anh Tran, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.
