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Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 1-6

Learning from Clostridium novyi-NT: How to defeat cancer

1 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang; Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Sichuan Medical University, Luzhou, China
2 Department of Medical Affair, Chengdu Military General Hospital, Chengdu, Sichuan, China
3 Department of Cardiology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
4 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Prof. Xinli Shi
Department of Immunology and Pathobiology, Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.204841

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 > Abstract 

Side effects associated with conventional anticancer therapies have prompted the new idea of solid tumor treatment strategy. One of them is using bacteria explored as potential antitumor agents over more than one century. Notably, the ideal therapy is a specifical target to tumors with limited toxicity. Here, we take “Clostridium novyi” for the search keyword in the PubMed from 2000 to 2015 and describe that C. novyi-NT spores act as “Trojan horse” for bacteriolytic therapy. This therapy is based on the fact that the live and attenuated obligate anaerobic bacteria are capable of binary fission selectively in anoxic areas of solid tumors and direct tumoricidal effects. Our succinct review mainly concentrates on the potential mechanisms of combination bacteriolytic therapy, an effective and safe tumor therapy with the help of C. novyi-NT. Importantly, C. novyi-NT spores were shown to induce solid tumor regression and exhibit the property to initiate an immune response. Therefore, C. novyi-NT spores should be an effective and safe tumor therapy.

Keywords: Anticancer agent, bacteriolytic therapy, Clostridium novyi-NT, immune response, solid tumor regression

How to cite this article:
Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: How to defeat cancer. J Can Res Ther 2018;14, Suppl S1:1-6

How to cite this URL:
Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: How to defeat cancer. J Can Res Ther [serial online] 2018 [cited 2022 May 19];14, Suppl S1:1-6. Available from: https://www.cancerjournal.net/text.asp?2018/14/8/1/204841

Li Wang and Xiaochao Tian contributed equally to this work.

 > Introduction Top

Cancer is a major public health problem in the world.[1] To some extent, surgery, radiotherapy, and chemotherapy are effective in the treatment of solid tumors.[2] However, they often have poor selectivity and drug resistance. Live bacteria (Clostridium novyi) can overcome these limitations in solid tumors.[3],[4] Over one century, bacterial sporad was observed to cause tumor regression.[5],[6] Bacteria, the optimal robot factory, have unique capabilities such as microenvironmental sensing, motility, intratumoral targeting, nutrient competition, extracellular enzymes, immunostimulation, and genetical modification.[7] For this reason, we intensely use bacteria to treat solid tumors.

 > Cancer Strike Back of Genusclostridium Top

Recently, Swee Hin Teoh group reported that heat-inactivated Clostridium sporogenes bacteria inhibit colorectal cancer cell proliferation on a three-dimensional platform.[8] In fact, as early as the year 1813, the loading-tumor patients were reported that tumor regression by clostridial gas gangrene.[9] In 1947, spores of Clostridium histolyticum, a pathogenic strain, were directly injected into the transplanted sarcomas in mice leading to significant tumor lysis.[10] Soon after, spores of a nonpathogenic strain, Clostridium tetani, were first injected intravenously into normal and tumor-bearing mice, in which the spores did not germinate in the organs and tissues. However, all tumor-bearing mice were died with tetanus within 48 h.[11] The experiment showed that intratumoral injection was unnecessary. In 1959, spores of another nonpathogenic strain, Clostridium butyricum M-55, did not show any antitumor activity.[12] Therefore, the bacterial sporadic trials were stagnant. However, at least these studies suggested that spores of nonpathogenic strains of genus Clostridium safely germinate in the hypoxia/necrotic regions of solid tumors. Up to the year 1994, the genetically modified Clostridium beijerinckii spores as the gene delivery vector were used to target human solid tumor therapy.[13],[14]


We take “Clostridium novyi” as the search keyword in the PubMed databases for data collection. Before 2000, no study reported the tumor regression of C. novyi. Most of the research focus on the pathogenicity factors of bacteria. Therefore, only 2000–2015 studies were considered. To rule out any bias, we have reviewed all articles in 2010–2015, which have searched for the association of C. novyi and tumor regression.

The research topics of these articles

In 2001, the combination spores of a new strain, C. novyi-NT, with conventional chemotherapeutic agents resulted in a significant tumor regression, which was called combination bacteriolytic therapy (COBALT).[15] In 2002, a strain of C. butyricum genetically modified to express the deaminase,  Escherichia More Details coli enzyme cytosine, was used in the clinical studies for clostridial-dependent enzyme prodrug therapy.[16] In addition, Clostridium-directed antibody therapy is a combination of the oncolytic properties of C. novyi-NT with the target selectivity of antibody therapeutics, in which the bacteria used as carrier-expressed single-chain antibodies specific for human hypoxia-inducible factor 1 alpha, targeting the most resistant regions in human solid cancer.[17] Today, C. novyi-NT is the only Clostridium strain enrolled as an anticancer agent to investigate in human trials.[7],[18],[19],[20] Systemic injection of C. novyi-NT spores is also on the way (www.clinicaltrials.gov/ct). In 2006, Sciencereported that C. novyi enhances the release and efficacy of liposomal cancer drugs.[21] Recently, several studies have developed novel antitumor approaches using C. novyi-NT spores, such as lung neoplasms, malignant mesenchymal tumor, pancreatic cancer, soft-tissue sarcoma, stomach carcinoma, and urinary bladder neoplasms (www.clinicaltrials.gov/ct). [Table 1] lists all the cites suggested. This will provide total information for the cancer bacteria therapy related to C. novyi-NT.
Table 1: Schematic overview of candidate strains related to C. novyi-NT for cancer treatment

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 > Clostridium Novyi -Nt: from Pathogen to an Attenuated Strain Top

C. novyi is a Gram-positive spore-forming anaerobe,[22] which is a soil organism implicated in wound-associated gas gangrene.[23],[24],[25],[26] High rate C. novyi infection was reported in person who injects drugs.[27],[28]

Wild-type C. novyi is a pathogen that produces α-toxin, a lethal toxin.[24] The α-toxin is a glycosylated cellular GTPase protein, which uses UDP-GlcNAc as a sugar donor [29],[30] and targets cellular GTPase proteins leading to actin cytoskeletal disruption and cell death.[24],[31] According to the distribution in the necrotic regions when injected intravenously, the Vogelstein group selected C. novyi among 26 different strains tested, including genus Bifidobacterium, Lactobacillus, and Clostridium, and prepared the attenuated C. novyi-NTspores [Figure 1].[15] To eliminate the bacteriophage carrying the lethal a-toxin gene, C. novyi spores are heated at 70°C for 15 min.[32] The heat attenuated strain, C. novyi-NT, is generated by screening for the C. novyi-NTspores that have lost the prophage.[15] C. novyi-NThas a number of features favorable for cancer therapy. Especially, C. novyi-NT spores are easier to store, handle, and stable to nonpermissive conditions.
Figure 1: Proposed model of Clostridium novyi-NT spores eliminates solid tumors in combination bacteriolytic therapy

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Effectivity concerns

C. novyi-NT spores have been experimentally tested as an antitumor agent in animal studies and clinical trials.[19] Interestingly, dramatic tumor regressions were observed after treatment with C. novyi-NT spores and a microtubule-binding agent, dolastatin-10, or a DNA damaging agent, mitomycin C, in nude mice loading colorectal cancer cell line HCT116. The strategy was named COBALT.[15] Surprisingly, treatment with such strategy cured about 30% of mice loading tumors.[33] However, they also found that approximately 15% mortality due to tumor lysis syndrome, which was associated with the tumor size.[15]

Furthermore, combination of C. novyi-NT spores with radiation [34] or anti-vascular chemotherapeutic agents [35],[36] was subsequently determined the antitumor effect and reduced the tumor lysis syndrome. As the radio-enhancing agent, C. novyi-NT spores were used in combination with low-dose radiation, which overcome the hypoxic barriers and resulted in tumor regressions with relatively little toxicity.[34] Microtubule synthesis inhibitor resulted in slower tumor regressions than microtubule stabilizer through enlarging the hypoxic regions, in which C. novyi-NT spores germinated.[35] Accordingly, the combination of C. novyi-NT spores with a microtubule-stabilizing agent (e.g., discodermolide analogs) causes rapid and complete tumor regression in HCT116 tumor-bearing nude mice.[37]

Recently, one study provided evidence that C. novyi-NT spores result in glioblastoma, a highly aggressive primary brain tumor, localized germination, tumor destruction, and a significant survival benefit in tumor-bearing rats.[38]

Safety concerns

An ideal anticancer bacterium should be safety, effectivity, selectivity, chemotaxis, and nonimmunogenicity.[7],[39]Clostridia in the blood stream can be eliminated with the use of antibiotics such as metronidazole.[40] The genome and transcriptome of C. novyi-NT have been sequenced and determined.[41] In animal studies, systemic-administered C. novyi-NT spores have no clinical toxicity and were rapidly cleared by the reticuloendothelial system in healthy mice or rabbits.[42] Meanwhile, toxicosis induced by dose administration of C. novyi-NT spores is manageable in natural tumor-bearing dogs.[43] Today, three Phase 1 trials of COBALT about C. novyi-NT spores in patients are in progress (www.clinicaltrials.gov/ct).

In addition, C. novyi-NT can be used to evaluate the bacteriolytic therapies, in which a noninvasive magnetic resonance imaging method was developed for imaging of the distribution, accumulation, germination, and clearance of injected tumor-homing bacteria.[19],[44]

 > Proposed Mechanism Top

Tumor environmental and genetic mechanisms influence tumor angiogenesis and growth, resulting in the formation of defective blood vessels, heterogeneous blood flow, and the emergence of hypoxic/anoxic necrotic areas.[45],[46],[47] The unique solid immune-privileged tumor microenvironment, which features low oxygen and abundant nutrients,[48],[49] provides a haven for anaerobic bacteria.[50]

Systemically administered C. novyi-NT spores are distributed throughout the body but germinate only within anoxic areas of tumors.[33] Once germinated, the bacteria secrete extracellular enzymes,such as phospholipase C, proteases, and lipases, destroy adjacent cancer cells, trigger host inflammatory responses, induce antitumor immunity and tumor destruction.[21],[41],[51] At the same time, C. novyi- NT spores act as an adjuvant to stimulate immune response [Figure 1].

There are some controversy ideas about the immune-mediated mechanism. Vogelsteingroup proposed that C. novyi- NT spores act as an adjuvant to initiatethe inflammatory reaction and stimulate the CD8+ T cell-mediated cellular immune response, which can subsequently destroy residual tumor cells not lysed by the bacteria and partially protect from the same tumor rechallenge.[33] However, Maletzki et al. group showed that only injection of C. novyi-NT spores irritated the innate immune response.[52] In their study, levels of CD4+ T cells, CD8+ T cells, and B cells in the leukocytes of circulation and spleens were similar to controls. Furthermore, the protective immune memory responses to tumor and noncancer cells were nonspecific. Interestingly, the numbers of natural killer (NK) cells increased in the leukocytes of circulation and spleens. Therefore, the study reported that the bacteriolytic therapy due to the bacterium-induced NK cell-mediated innate immune response.[52] Further, the group used live Streptococcus pyogenes to treat pancreatic carcinoma and showed that not only the direct bacteriolytic activity but also the innate immune response induced by disseminated tumor components from damaged tumor cells.[53],[54]

In a word, C. novyi- NT-induced tumor regression within anoxic areas of tumors through bacteriolysis (e.g., direct competition for nutrients, localized production of extracellular enzymes), breaking the tumor-induced tolerance, and development of the immune response (e.g., inflammatory responses, innate immune, and/or adaptive immune) [Figure 2]a. The cure rate and tumor lysis syndrome of C. novyi-NT are related to the balance between bacteriolysis, angiogenesis, immune response, and tumor size [Figure 2]b.[33],[52] However, the interplay between C. novyi- NT and immune response is a complex and largely unresolved matter, which influences tumor angiogenesis and growth.
Figure 2: Working model of C. novyi-NT in tumor regression and the major problems in current therapy. (a) C. novyi-NT induced tumor regression in anoxic areas of tumors via bacteriolysis-induced immune response. (b) The cure rate and tumor lysis syndrome of C. novyi-NT are related to the balance between bacteriolysis, angiogenesis, immune response, and tumor size. (c) The major problems in current cancer bacteria therapy related to C. novyi-NT

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 > Future Perspectives Top

We are hopeful that the full potential of C. novyi-NT-mediated solid tumor regression will become clear and reality. Therefore, we show the major problems in the current therapy in [Figure 2]c. How to control the speed of tumor regression to avoid animal death or the tumor lysis syndrome in large-sized solid tumor?[15] More research is required to determine the relationship between tumor size and C. novyi-NT usage. One group proposed the pacemaker model,[55] a working hypothesis about the Clostridium proliferation within hypoxic micro-niches. Application of the hypothesis to reveal the above question in clinical trials still has a long way to go.

Owing to several unanswered questions, caution is needed. For example, it is important to learn more about the relationship between C. novyi-NT growth and the tumor cells sensing hypoxia in the solid tumor microenvironment.[56] An important direction is that C. novyi-NT was used to detect and target solid tumors. For example, staining C. novyi-NT with semiconductor nanocrystals was used as a means to detect and target neoplastic tumors.[57]

 > Conclusions Top

Modified C. novyi-NT spores acted as carrier-targeting hypoxic regions in human solid cancer.[17] In addition, C. novyi-NT secreted a novel lipase contribute to the release of liposome-encapsulated drugs within tumors.[21],[51] Especially, intratumoral injection C. novyi-NTspores prolonged survival in rats with glioma and produced an objective response in six dogs and a human patient with soft-tissue sarcomas.[58] Therefore, C. novyi- NT spores could serve as an alternative for solid tumor therapy although the precise mechanism requires further studies.

Financial support and sponsorship

This work was financially supported by the Youth Foundation of Hebei Educational Committee of China (No. QN2014012), the Research Fund for the Doctoral Program of Hebei University of Traditional Chinese Medicine (No. BSZ2015006), and the Research Fund from Hebei Key Laboratory of Integrative Medicine on Liver-kidney patterns.

Conflicts of interest

There are no conflicts of interest.

 > References Top

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.  Back to cited text no. 1
Cao S, Cripps A, Wei MQ. New strategies for cancer gene therapy: Progress and opportunities. Clin Exp Pharmacol Physiol 2010;37:108-14.  Back to cited text no. 2
Ben-Jacob E, Coffey DS, Levine H. Bacterial survival strategies suggest rethinking cancer cooperativity. Trends Microbiol 2012;20:403-10.  Back to cited text no. 3
Zu C, Wang J. Tumor-colonizing bacteria: A potential tumor targeting therapy. Crit Rev Microbiol 2014;40:225-35.  Back to cited text no. 4
Leschner S, Weiss S. Salmonella-allies in the fight against cancer. J Mol Med (Berl) 2010;88:763-73.  Back to cited text no. 5
Linnebacher M, Maletzki C, Klier U, Klar E. Bacterial immunotherapy of gastrointestinal tumors. Langenbecks Arch Surg 2012;397:557-68.  Back to cited text no. 6
Forbes NS. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 2010;10:785-94.  Back to cited text no. 7
Bhave MS, Hassanbhai AM, Anand P, Luo KQ, Teoh SH. Effect of heat-inactivated Clostridium sporogenes and its conditioned media on 3-dimensional colorectal cancer cell models. Sci Rep 2015;5:15681.  Back to cited text no. 8
Minton NP. Clostridia in cancer therapy. Nat Rev Microbiol 2003;1:237-42.  Back to cited text no. 9
Parker RC, Plummer HC, Siebenmann CO, Chapman MG. Effect of histolyticus infection and toxin on transplantable mouse tumors. Exp Biol Med 1947;66:461-7.  Back to cited text no. 10
Malmgren RA, Flanigan CC. Localization of the vegetative form of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Res 1955;15:473-8.  Back to cited text no. 11
Möse JR, Möse G. Experiments on serologic tumor diagnosis, using spore-forming bacteria (II). Z Krebsforsch 1970;74:91-9.  Back to cited text no. 12
Lemmon MJ, van Zijl P, Fox ME, Mauchline ML, Giaccia AJ, Minton NP, et al. Anaerobic bacteria as a gene delivery system that is controlled by the tumor microenvironment. Gene Ther 1997;4:791-6.  Back to cited text no. 13
Lemmon M, Elwell J, Brehm J, Mauchline M, Minton N, Giaccia A, et al. Anaerobic bacteria as a gene delivery system to tumors. Cancer Res 1994;35:879-91.  Back to cited text no. 14
Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci U S A 2001;98:15155-60.  Back to cited text no. 15
Liu SC, Minton NP, Giaccia AJ, Brown JM. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 2002;9:291-6.  Back to cited text no. 16
Groot AJ, Mengesha A, van der Wall E, van Diest PJ, Theys J, Vooijs M. Functional antibodies produced by oncolytic clostridia. Biochem Biophys Res Commun 2007;364:985-9.  Back to cited text no. 17
Pawelek JM, Low KB, Bermudes D. Bacteria as tumour-targeting vectors. Lancet Oncol 2003;4:548-56.  Back to cited text no. 18
Murthy SH, Thorunn H, Janku F. Phase 1 trial of image-guided oncolysis by Clostridium novyi-NT spore inoculation: Early technical insights. J Vasc Interv Radiol 2015;26:151-6.  Back to cited text no. 19
Wei MQ, Mengesha A, Good D, Anné J. Bacterial targeted tumour therapy-dawn of a new era. Cancer Lett 2008;259:16-27.  Back to cited text no. 20
Cheong I, Huang X, Bettegowda C, Diaz LA Jr., Kinzler KW, Zhou S, et al. A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science 2006;314:1308-11.  Back to cited text no. 21
Plomp M, McCaffery JM, Cheong I, Huang X, Bettegowda C, Kinzler KW, et al. Spore coat architecture of Clostridium novyi NT spores. J Bacteriol 2007;189:6457-68.  Back to cited text no. 22
Abdel-Haq NM, Chearskul P, Salimnia H, Asmar BI. Clostridial liver abscess following blunt abdominal trauma: Case report and review of the literature. Scand J Infect Dis 2007;39:734-7.  Back to cited text no. 23
Aronoff DM. Clostridium novyi, sordellii, and tetani: Mechanisms of disease. Anaerobe 2013;24:98-101.  Back to cited text no. 24
Badenoch PR, Mills RA, Woolley MW, Wetherall BL. Clostridium novyi keratitis. Br J Ophthalmol 2007;91:691.  Back to cited text no. 25
Ma M, Boyd JT, Trinh HT, Coombs JW, Fermann GJ. Fatal myocarditis due to Clostridium novyi type B in a previously healthy woman: Case report and literature review. Scand J Infect Dis 2007;39:77-80.  Back to cited text no. 26
Finn SP, Leen E, English L, O'Briain DS. Autopsy findings in an outbreak of severe systemic illness in heroin users following injection site inflammation: An effect of Clostridium novyi exotoxin? Arch Pathol Lab Med 2003;127:1465-70.  Back to cited text no. 27
Palmateer NE, Hope VD, Roy K, Marongiu A, White JM, Grant KA, et al. Infections with spore-forming bacteria in persons who inject drugs, 2000-2009. Emerg Infect Dis 2013;19:29-34.  Back to cited text no. 28
Guttenberg G, Papatheodorou P, Genisyuerek S, Lü W, Jank T, Einsle O, et al. Inositol hexakisphosphate-dependent processing of Clostridium sordellii lethal toxin and Clostridium novyi α-toxin. J Biol Chem 2011;286:14779-86.  Back to cited text no. 29
Selzer J, Hofmann F, Rex G, Wilm M, Mann M, Just I, et al. Clostridium novyi alpha-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J Biol Chem 1996;271:25173-7.  Back to cited text no. 30
Belyi Y, Aktories K. Bacterial toxin and effector glycosyltransferases. Biochim Biophys Acta 2010;1800:134-43.  Back to cited text no. 31
Nishida S, Nakagawara G. Relationship between toxigenicity and sporulating potency of Clostridium novyi. J Bacteriol 1965;89:993-5.  Back to cited text no. 32
Agrawal N, Bettegowda C, Cheong I, Geschwind JF, Drake CG, Hipkiss EL, et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc Natl Acad Sci U S A 2004;101:15172-7.  Back to cited text no. 33
Bettegowda C, Dang LH, Abrams R, Huso DL, Dillehay L, Cheong I, et al. Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria. Proc Natl Acad Sci U S A 2003;100:15083-8.  Back to cited text no. 34
Dang LH, Bettegowda C, Agrawal N, Cheong I, Huso D, Frost P, et al. Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agents. Cancer Biol Ther 2004;3:326-37.  Back to cited text no. 35
Folkman J. A novel anti-vascular therapy for cancer. Cancer Biol Ther 2004;3:338-9.  Back to cited text no. 36
Smith AB 3rd, Freeze BS, LaMarche MJ, Sager J, Kinzler KW, Vogelstein B. Discodermolide analogues as the chemical component of combination bacteriolytic therapy. Bioorg Med Chem Lett 2005;15:3623-6.  Back to cited text no. 37
Staedtke V, Bai RY, Sun W, Huang J, Kibler KK, Tyler BM, et al. Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats. Oncotarget 2015;6:5536-46.  Back to cited text no. 38
Jain RK, Forbes NS. Can engineered bacteria help control cancer? Proc Natl Acad Sci U S A 2001;98:14748-50.  Back to cited text no. 39
Nuyts S, Van Mellaert L, Theys J, Landuyt W, Lambin P, Anné J. Clostridium spores for tumor-specific drug delivery. Anticancer Drugs 2002;13:115-25.  Back to cited text no. 40
Bettegowda C, Huang X, Lin J, Cheong I, Kohli M, Szabo SA, et al. The genome and transcriptomes of the anti-tumor agent Clostridium novyi-NT. Nat Biotechnol 2006;24:1573-80.  Back to cited text no. 41
Diaz LA Jr., Cheong I, Foss CA, Zhang X, Peters BA, Agrawal N, et al. Pharmacologic and toxicologic evaluation of C. novyi-NT spores. Toxicol Sci 2005;88:562-75.  Back to cited text no. 42
Krick EL, Sorenmo KU, Rankin SC, Cheong I, Kobrin B, Thornton K, et al. Evaluation of Clostridium novyi-NT spores in dogs with naturally occurring tumors. Am J Vet Res 2012;73:112-8.  Back to cited text no. 43
Liu G, Bettegowda C, Qiao Y, Staedtke V, Chan KW, Bai R, et al. Noninvasive imaging of infection after treatment with tumor-homing bacteria using Chemical Exchange Saturation Transfer (CEST) MRI. Magn Reson Med 2013;70:1690-8.  Back to cited text no. 44
Philip B, Ito K, Moreno-Sánchez R, Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 2013;34:1699-707.  Back to cited text no. 45
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57.  Back to cited text no. 46
Jain RK. Determinants of tumor blood flow: A review. Cancer Res 1988;48:2641-58.  Back to cited text no. 47
Cummins J, Tangney M. Bacteria and tumours: Causative agents or opportunistic inhabitants? Infect Agent Cancer 2013;8:11.  Back to cited text no. 48
Streilein JW. Unraveling immune privilege. Science 1995;270:1158-9.  Back to cited text no. 49
Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437-47.  Back to cited text no. 50
Cheong I, Huang X, Thornton K, Diaz LA Jr., Zhou S. Targeting cancer with bugs and liposomes: Ready, aim, fire. Cancer Res 2007;67:9605-8.  Back to cited text no. 51
Maletzki C, Gock M, Klier U, Klar E, Linnebacher M. Bacteriolytic therapy of experimental pancreatic carcinoma. World J Gastroenterol 2010;16:3546-52.  Back to cited text no. 52
Linnebacher M, Maletzki C, Emmrich J, Kreikemeyer B. Lysates of S. pyogenes serotype M49 induce pancreatic tumor growth delay by specific and unspecific antitumor immune responses. J Immunother 2008;31:704-13.  Back to cited text no. 53
Maletzki C, Linnebacher M, Kreikemeyer B, Emmrich J. Pancreatic cancer regression by intratumoural injection of live Streptococcus pyogenes in a syngeneic mouse model. Gut 2008;57:483-91.  Back to cited text no. 54
Schmidt W, Fabricius EM, Schneeweiss U. The tumour-Clostridium phenomenon: 50 years of developmental research (Review). Int J Oncol 2006;29:1479-92.  Back to cited text no. 55
Harris AL. Hypoxia – A key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38-47.  Back to cited text no. 56
Xie J, Cao S, Good D, Wei M, Ren X. Combination of a fluorescent dye and a Zn-S cluster and its biological application as a stain for bacteria. Inorg Chem 2010;49:1319-21.  Back to cited text no. 57
Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med 2014;6:249ra111.  Back to cited text no. 58


  [Figure 1], [Figure 2]

  [Table 1]

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