Colonisation ofClostridiumin the body is restricted to hypoxic and necrotic areas of tumours

Lambin, Philippe; Theys, Jan; Landuyt, Willy; Rijken, P.F.J.W.; Kogel, Albert van der; Schueren, E. van der; Hodgkiss, R.J.; Fowler, Jack F.; Nuyts, Sandra; Bruijn, Ernst de; Mellaert, Lieve Van; Anné, Jozef

doi:10.1006/anae.1998.0161

Cited by 93 publications

(75 citation statements)

References 18 publications

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“…At the end of the follow-up period, or when tumours outranged the ethically allowed maximal volume, animals were killed by cervical dislocation. Tumours and normal tissues (liver, spleen) were excised, grinded and examined for colonisation levels at different time points using a procedure described previously (Lambin et al, 1998).…”

Section: In Vivo Evaluation Of Antitumour Effectmentioning

confidence: 99%

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo

et al. 2006

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The unique properties of the tumour microenvironment can be exploited by using recombinant anaerobic clostridial spores as highly selective gene delivery vectors. Although several recombinant Clostridium species have been generated during the past decade, their efficacy has been limited. Our goal was to substantially improve the prospects of clostridia as a gene delivery vector. Therefore, we have assessed a series of nitroreductase (NTR) enzymes for their capacity to convert the innocuous CB1954 prodrug to its toxic derivative. Among the enzymes tested, one showed superior prodrug turnover characteristics. In addition, we established an efficient gene transfer procedure, based on conjugation, which allows for the first time genetic engineering of Clostridium strains with superior tumour colonisation properties with high success rates. This conjugation procedure was subsequently used to create a recombinant C. sporogenes overexpressing the isolated NTR enzyme. Finally, analogous to a clinical setting situation, we have tested the effect of multiple consecutive treatment cycles, with antibiotic bacterial clearance between cycles. Importantly, this regimen demonstrated that intravenously administered spores of NTR-recombinant C. sporogenes produced significant antitumour efficacy when combined with prodrug administration.

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Section: In Vivo Evaluation Of Antitumour Effectmentioning

confidence: 99%

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo

et al. 2006

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“…Indeed, the vast majority of members belonging to this class and genus are completely harmless and do not cause any known human disease. In fact, some strains, such as C. sporogenes and C. novyi, have been employed as anticancer drug delivery systems that specifically target hypoxic and necrotic areas of tumors albeit in animal models (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

The Clostridium Sporulation Programs: Diversity and Preservation of Endospore Differentiation

Al-Hinai

Jones

Papoutsakis

2015

Microbiol Mol Biol Rev

158

190

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SUMMARY Bacillus and Clostridium organisms initiate the sporulation process when unfavorable conditions are detected. The sporulation process is a carefully orchestrated cascade of events at both the transcriptional and posttranslational levels involving a multitude of sigma factors, transcription factors, proteases, and phosphatases. Like Bacillus genomes, sequenced Clostridium genomes contain genes for all major sporulation-specific transcription and sigma factors ( spo0A , sigH , sigF , sigE , sigG , and sigK ) that orchestrate the sporulation program. However, recent studies have shown that there are substantial differences in the sporulation programs between the two genera as well as among different Clostridium species. First, in the absence of a Bacillus -like phosphorelay system, activation of Spo0A in Clostridium organisms is carried out by a number of orphan histidine kinases. Second, downstream of Spo0A, the transcriptional and posttranslational regulation of the canonical set of four sporulation-specific sigma factors (σ F , σ E , σ G , and σ K ) display different patterns, not only compared to Bacillus but also among Clostridium organisms. Finally, recent studies demonstrated that σ K , the last sigma factor to be activated according to the Bacillus subtilis model, is involved in the very early stages of sporulation in Clostridium acetobutylicum , C. perfringens , and C. botulinum as well as in the very late stages of spore maturation in C. acetobutylicum . Despite profound differences in initiation, propagation, and orchestration of expression of spore morphogenetic components, these findings demonstrate not only the robustness of the endospore sporulation program but also the plasticity of the program to generate different complex phenotypes, some apparently regulated at the epigenetic level.

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“…The crucial question of efficient colonizing tumours of smaller size (<3 cm 3 ) has been adressed with experiments using vascular targeting compounds combined with the vector system 'Clostridium sporogenes' to be tested in syngeneic rat rhabdomyosarcomas after both Clostridium acetobutylicum and Clostridium oncolyticum, following systemic administration, had displayed superior colonization capacity (118,119). Among smaller tumours of <1 cm 3 there were such with little hypoxia and no necrosis.…”

Section: Clostridia-directed Enzyme Prodrug-therapy (Cdept)mentioning

confidence: 99%

The tumour-Clostridium phenomenon: 50 years of developmental research (Review)

Schmidt

Fabricius²,

Schneeweiss³

2006

Int J Oncol

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Abstract. The tumour-Clostridium phenomenon describes the specific affinity of spore forming anaerobes to tumour growth. The discovery of strictly intratumoral tetanus toxicoinfections in tumour-bearing mice after intravenous spore administration gave the impulse to search for non-toxic clostridial isolates with tumour-selective properties for clostridial biotherapy, i.e. oncolysis, as well as serologic tumour diagnostics without any toxic side-effects. Systematic studies of the oncolytic process and its variables on diverse experimental tumours and laboratory animals revealed that tumour liquefaction, converting necrotic tumour parts to putrid abscesses filled with masses of clostridial forms, stops sharply at the viable rim of the blood-supplied tumour tissue. Similar results were observed in clinical trials, particular of gliomas. Before oncolysis is initiated, the first stage of clostridial multiplication in the vascularized tissue is inducing a humoural immune response, preceded by phagocytic activity. The majority of tumour-bearing laboratory and domestic animals, so far tested serologically, clinical cancer patients as well, responded with anti-rod antibodies and, independently, antispore antibodies. Oncolytic and non-oncolytic Clostridia were equally immunogenic. During the early, immunizing period of clostridial proliferation, analytical tumour-tetanus experiments were focused on potential relations between tumour growth kinetics and rod proliferation. Based on realistic growth models and target principles, computer simulations could reproduce the results, i.e. cumulative curves of tetanus lethality in groups of mice. Thus, crucial assumptions of the mathematical model were ex post confirmed by further experiments. Our working hypothesis concentrates on temporally hypoxic micro-niches close to a pre-mitotic cell with enhanced oxygen demand which can be utilized by anaerobes (randomly) located there. As early immune reactions to clostridial antigens via phagocytosis and humoural immune response will do without invasion in necrobiotic avascular tumour areas, the pacemaker model of tumour-Clostridium interplay extends the scope of genetically engineered Clostridia to early treatment of metastases. Thus, novel concepts, such as 'Clostridia-directed enzyme prodrugtherapy' and 'Combined bacteriolytic therapy', together with immune activation, can come into play.

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Colonisation ofClostridiumin the body is restricted to hypoxic and necrotic areas of tumours

Cited by 93 publications

References 18 publications

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo

Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo

The Clostridium Sporulation Programs: Diversity and Preservation of Endospore Differentiation

The tumour-Clostridium phenomenon: 50 years of developmental research (Review)

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