Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis

Liu, S C; Minton, Nigel P.; Giaccia, Amato J.; Brown, J. Martin

doi:10.1038/sj.gt.3301659

Cited by 178 publications

(126 citation statements)

References 12 publications

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“…A method of transforming the selected species, C. sporogenes, has previously been described (Liu et al, 2002). However, repeated attempts to obtain transformants with this method of two different C. sporogenes strains and of C. novyi-NT in our laboratories over a period of 2 years were unsuccessful.…”

Section: Isolation Of Novel Ntr Enzymementioning

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: Isolation Of Novel Ntr Enzymementioning

confidence: 99%

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

et al. 2006

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“…34 Other types of bacteria are currently being developed as anticancer agents. [6][7][8][9][10]35 In these strategies, spores of anaerobic bacteria are injected and selectively grow within the necrotic regions of tumours where they find a niche to grow. For example, C. novyi has shown some dramatic antitumour effects in combination with conventional chemotherapeutic drugs 35 and Salmonella are capable of targeting, colonizing and eliciting growth suppression of tumours in mice.…”

Section: Invasive E Coli As a Therapeutic Delivery Vector Rj Critchlmentioning

confidence: 99%

“…More recently, this concept has been re-evaluated using attenuated strains of Salmonella 6,7 and Clostridium. [8][9][10] A genetically attenuated strain of Salmonella (VNP20009) 7 was recently used in a clinical trial. 11 VNP20009 demonstrated marked toxicity when injected above 3 Â 10 8 CFU/m 2 .…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic applications of recombinant, invasive E. coli

et al. 2004

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“…For gene therapy, bacterial spores can be genetically engineered to express multiple therapeutic transgenes, and if necessary, their spread can be controlled with antibiotics. Examples of prokaryotic vectors include bacteria of the genera Clostridium (Fox et al, 1996;Lemmon et al, 1997;Liu et al, 2002), Bifidobacterium (Yazawa et al, 2000), and Salmonella auxotroph (Pawelek et al, 1997). Tumor selective spore germination was observed in rhabdomyosarcoma-bearing rats injected with five different obligate anaerobe strains, the most efficient species being C. acetobutylicum (Lambin et al, 1998), and C. oncolyticum (Lambin et al, 1998).…”

Section: Hypoxia-targeted Gene Deliverymentioning

confidence: 99%

“…The therapeutic potential of the bacterial delivery of a GDEPT approach was demonstrated in vitro, with the conversion of the prodrug CB1954 into a cytotoxic agent by Clostridia-produced NTR (Fox et al, 1996;Lemmon et al, 1997). Also, intravenous injection of spores of C. sporogens transfected with the gene encoding the enzyme CD, followed by systemic administration of 5-FC, induced significant activity against SCCVII tumors transplanted into syngeneic C3H/Km mice (Liu et al, 2002). For combined gene therapy and radiotherapy, C. acetobutylicum spores were modified to express TNF-a under the control of the radiation-responsive prokaryotic promoter from the recA gene .…”

Section: Hypoxia-targeted Gene Deliverymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis

Cited by 178 publications

References 12 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

Potential therapeutic applications of recombinant, invasive E. coli

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

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