Pharmacologic and Toxicologic Evaluation of C. novyi-NT Spores

Díaz, Luis A.; Cheong, Ian; Foss, Catherine A.; Zhang, Xiaosong; Peters, Brock A.; Agrawal, Nishant; Bettegowda, Chetan; Karim, Baktiar O.; Liu, Guosheng; Khan, Khalid M.; Huang, Xin; Kohli, Manu; Dang, Long H.; Hwang, Paul A.; Vogelstein, Ahava; Garrett‐Mayer, Elizabeth; Kobrin, Barry J.; Pomper, Martin G.; Zhou, Shibin; Kinzler, Kenneth W.; Vogelstein, Bert; Huso, David L.

doi:10.1093/toxsci/kfi316

Cited by 99 publications

(116 citation statements)

References 37 publications

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“…In initial experiments with C. novyi-NT, 10% to 25% of animals with large tumors died after receiving therapeutic doses of C. novyi-NT spores (17). However, toxicity could be effectively controlled by simple hydration (20).…”

Section: Introductionmentioning

confidence: 99%

Targeted Therapy with aSalmonella TyphimuriumLeucine-Arginine Auxotroph Cures Orthotopic Human Breast Tumors in Nude Mice

Zhao

Yang²,

Ma³

et al. 2006

Cancer Research

284

240

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Section: Introductionmentioning

confidence: 99%

Targeted Therapy with aSalmonella TyphimuriumLeucine-Arginine Auxotroph Cures Orthotopic Human Breast Tumors in Nude Mice

Zhao

Yang²,

Ma³

et al. 2006

Cancer Research

284

240

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“…Intravenous injection of C. novyi NT spores into tumor-bearing mice was found to successfully eradicate large tumors, either in combination with radiation therapy (7) and chemotherapy (13) or by itself, since it can induce a potent immune response (1). When C. novyi NT spores are injected into mice, the spores exclusively germinate in tumors and spare other tissues, even in aged animals or those with ischemic myocardial lesions (16).…”

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confidence: 99%

Spore Coat Architecture of Clostridium novyi NT Spores

et al. 2007

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Spores of the anaerobic bacterium Clostridium novyi NT are able to germinate in and destroy hypoxic regions of tumors in experimental animals. Future progress in this area will benefit from a better understanding of the germination and outgrowth processes that are essential for the tumorilytic properties of these spores. Toward this end, we have used both transmission electron microscopy and atomic force microscopy to determine the structure of both dormant and germinating spores. We found that the spores are surrounded by an amorphous layer intertwined with honeycomb parasporal layers. Moreover, the spore coat layers had apparently selfassembled, and this assembly was likely to be governed by crystal growth principles. During germination and outgrowth, the honeycomb layers, as well as the underlying spore coat and undercoat layers, sequentially dissolved until the vegetative cell was released. In addition to their implications for understanding the biology of C. novyi NT, these studies document the presence of proteinaceous growth spirals in a biological organism.Clostridium novyi is a motile, spore-forming, gram-variable (gram positive in young cultures, often gram negative in older cultures) anaerobic bacterium. It can cause infections leading to gas gangrene in humans, particularly after traumatic wounds or illicit drug use, and can also infect domestic animals, particularly sheep (22). The pathology of C. novyi is attributed to the lethal alpha-toxin (6). To reduce systemic toxicity, an attenuated strain, called C. novyi NT and devoid of the alphatoxin, was generated. Intravenous injection of C. novyi NT spores into tumor-bearing mice was found to successfully eradicate large tumors, either in combination with radiation therapy (7) and chemotherapy (13) or by itself, since it can induce a potent immune response (1). When C. novyi NT spores are injected into mice, the spores exclusively germinate in tumors and spare other tissues, even in aged animals or those with ischemic myocardial lesions (16).C. novyi NT is therefore one of the most promising bacterial agents for cancer therapeutics that have been described in the past few years (55). Such therapeutic approaches were first attempted more than 50 years ago and have continued sporadically since that time. Many of these attempts used various strains of clostridia. Despite this long history and the importance of clostridia spores in other medical contexts, there have been relatively few studies of either the nature of the germination and outgrowth processes or the structure of the spore coat. Germination is a well-defined process of conversion of a dormant spore into a metabolically active form (46). The outgrowth stage starts with the initiation of spore metabolism. During the outgrowth stage, macromolecular synthesis in the spore converts the germinated spore into a growing cell (35,46). The spore coat endows bacterial spores with remarkable resistance to physical and chemical agents and allows them to persist in nature for centuries (11,17,57).Atomic for...

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“…Dichos autores no observaron toxicidad clínica ni en animales sanos, ni en aquellos que albergaban lesiones pobremente vascularizadas no neoplasicas, anteriores a la dosificación, tales como infartos de miocardio, Diaz et al, (2005).…”

Section: Combinación Con Otras Terapiasunclassified

Esporos bacterianos para el tratamiento del cáncer.

González¹,

Lencioni²,

Jiménez³

et al. 2012

Revista Complutense De Ciencias Veterinarias

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RESUMENLos métodos utilizados actualmente en el tratamiento del cáncer son todavía muy lesivos para el organismo y en muchas ocasiones poco efectivos. Los tumores sólidos con zonas de hipoxia presentan los mayores inconvenientes para su resolución. En las investigaciones sobre alternativas para su tratamiento, son muchos científicos los que apuestan por el uso de bacterias y por sus formas de resistencia, los esporos.Diferentes investigaciones realizadas han comprobado las ventajas del empleo de esporos bacterianos (Clostridium novyi-NT, Clostridium sporogenes ATCC13732, y Clostridium beijerinckii NCIMB 8052). Se caracterizan por ser estables hasta alcanzar zonas con las condiciones concretas permisivas para su germinación (hipoxia), por lo que pueden ser administrados por vía sistémica. El efecto antitumoral producido se basa en la producción de enzimas hidrolíticas (proteasas, nucleasas y lipasas) y, en la competición entre la bacteria y las células neoplásicas por los nutrientes. Así mismo, mediante técnicas de modificación del genoma, se han podido suprimir los genes perjudiciales e insertar diversos genes y plásmidos terapéuticos de acción selectiva en el tumor. Y por último, pueden combinarse con otros tratamientos (COBALT combination bacteriolytic therapy).El uso de esporos modificados genéticamente supone un nuevo horizonte en el tratamiento del cáncer, sobre todo en regiones inaccesibles del tumor.Palabras clave: esporos, cáncer, Clostridium novyi -NT,

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Pharmacologic and Toxicologic Evaluation of C. novyi-NT Spores

Cited by 99 publications

References 37 publications

Targeted Therapy with aSalmonella TyphimuriumLeucine-Arginine Auxotroph Cures Orthotopic Human Breast Tumors in Nude Mice

Targeted Therapy with aSalmonella TyphimuriumLeucine-Arginine Auxotroph Cures Orthotopic Human Breast Tumors in Nude Mice

Spore Coat Architecture of Clostridium novyi NT Spores

Esporos bacterianos para el tratamiento del cáncer.

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