Tumor-targeting prodrug-activating bacteria for cancer therapy

Cheng, C. C.; Lu, Yutong; Chuang, Kai‐Hsiang; Hung, Wen‐Chun; Shiea, Jentaie; Su, Yu-Cheng; Kao, Chien-Han; Chen, B. M.; Roffler, Steve R.; Cheng, Tian‐Lu

doi:10.1038/cgt.2008.10

Cited by 75 publications

(37 citation statements)

References 38 publications

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“…10,11 However, the most frequently used anti-cancer approach using bacteria is enzyme-prodrug therapy where systemically administered bacteria are used to deliver a gene/enzyme able to convert systemically administered prodrug into its active compound specifically in tumor tissue. [12][13][14] The utilization of bacterial systems for therapeutic purposes is further enhanced by genetic modifications, which make them a very promising tool for targeted delivery of genes and their products. Specific advantages of using bacteria for anti-cancer gene therapy include the natural oncolytic potential of some strains/species, direct targeting of tumor tissue and the ease of positive regulation/eradication.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

et al. 2011

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Several bacterial species have inherent ability to colonize solid tumors in vivo. However, their natural anti-tumor activity can be enhanced by genetic engineering that enables these bacteria express or transfer therapeutic molecules into target cells. In this review, we summarize latest research on cancer therapy using genetically modified bacteria with particular emphasis on blocking tumor angiogenesis. Despite recent progress, only a few recent studies on bacterial tumor therapy have focused on anti-angiogenesis. Bacteria-mediated anti-angiogenesis therapy for cancer, however, is an attractive approach given that solid tumors are often characterized by increased vascularization. Here, we discuss four different approaches for using modified bacteria as anti-cancer therapeutics-bactofection, DNA vaccination, alternative gene therapy and transkingdom RNA interference-with a specific focus on angiogenesis suppression. Critical areas and future directions for this field are also outlined.

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Section: Introductionmentioning

confidence: 99%

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

et al. 2011

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“…E. coli is part of the flora of the human GIT. Several studies have outlined the safety of IV administration of non-pathogenic E. coli strains to mice, and their ability to grow specifically within tumors 4,12 . E. coli MG1655 (as used in this study) also colonizes the mouse GIT to high levels 13 .…”

Section: Discussionmentioning

confidence: 99%

Bioluminescent Bacterial Imaging <em>In Vivo</em>

Baban

Cronin

Akin

et al. 2012

JoVE

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This video describes the use of whole body bioluminesce imaging (BLI) for the study of bacterial trafficking in live mice, with an emphasis on the use of bacteria in gene and cell therapy for cancer. Bacteria present an attractive class of vector for cancer therapy, possessing a natural ability to grow preferentially within tumors following systemic administration. Bacteria engineered to express the lux gene cassette permit BLI detection of the bacteria and concurrently tumor sites. The location and levels of bacteria within tumors over time can be readily examined, visualized in two or three dimensions. The method is applicable to a wide range of bacterial species and tumor xenograft types. This article describes the protocol for analysis of bioluminescent bacteria within subcutaneous tumor bearing mice. Visualization of commensal bacteria in the Gastrointestinal tract (GIT) by BLI is also described. This powerful, and cheap, real-time imaging strategy represents an ideal method for the study of bacteria in vivo in the context of cancer research, in particular gene therapy, and infectious disease. This video outlines the procedure for studying lux-tagged E. coli in live mice, demonstrating the spatial and temporal readout achievable utilizing BLI with the IVIS system. Video LinkThe video component of this article can be found at http://www.jove.com/video/4318/ Protocol 1. Tumor Induction 1. For routine tumor induction, the minimum tumorigenic dose of cells suspended in 200 μl of serum-free culture medium was injected subcutaneously (s.c.) into the flank of infection free 6-8 week old female Balb/C or athymic MF1-nu/nu mice n=6 (Harlan, Oxfordshire, UK) (1 x 10 6 4T1 cells) using a 21-gauge syringe needle. The viability of cells used for inoculation was greater than 95 % as determined by visual count using a haemocytometer and Trypan Blue Dye Exclusion (Gibco). 2. Following tumor establishment, tumors were allowed to grow and develop and were monitored twice weekly. Tumor volume was calculated according to the formula V=(ab 2 ) Π/6, where a is the longest diameter of the tumor and b is the longest diameter perpendicular to diameter a.

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“…Although methods for efficient enrichment of cancers by βG are still needed, several techniques are under development to preferentially accumulate βG in tumors, including antibody-directed enzyme prodrug therapy (22,27), genedirected enzyme prodrug therapy (19,20), and targeted bacterial expression of Escherichia coli βG (28). In addition, mutant human βG enzymes that display enhanced enzymatic activity at neutral pH values are being developed for selective activation of glucuronide drugs in tumors (33).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we tested the hypothesis that endogenously generated SN-38G is present in tumors at sufficient levels to contribute to the antitumor effects of CPT-11 therapy if it is reconverted to SN-38. As a model system, we used EJ human bladder cancer cells engineered to express membrane-tethered βG on their surface (EJ/mβG cells) to mimic the clinically relevant situations in which interstitial βG activity is naturally high (17) or artificially elevated by antibody, gene, or bacterial delivery methods (19,20,22,26,28). We found that after CPT-11 treatment, reconversion of endogenously produced SN38G to SN-38 in EJ/mβG bladder tumors significantly enhanced the anticancer efficacy of CPT-11.…”

Section: Discussionmentioning

confidence: 99%

Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

Prijovich

Chen

Roffler

2009

Molecular Cancer Therapeutics

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Irinotecan (CPT-11) is a clinically important anticancer prodrug that requires enzymatic hydrolysis by carboxyesterase to generate the active metabolite SN-38. However, SN-38 is further metabolized to inactive SN-38 glucuronide (SN-38G), thus diminishing the levels of active SN-38. Although exogenously administered glucuronide drugs are being investigated for cancer therapy, it is unknown if endogenously generated camptothecin glucuronide metabolites can be used for tumor therapy. Here, we tested the hypothesis that tumor-located hydrolysis of endogenously generated SN-38G can enhance the antitumor efficacy of CPT-11 therapy. EJ human bladder carcinoma cells expressing membrane-tethered β-glucuronidase (EJ/mβG cells) were used to selectively hydrolyze SN-38G to SN-38. Parental EJ and EJ/mβG cells displayed similar in vitro and in vivo growth rates and sensitivities to CPT-11 and SN-38. By contrast, EJ/mβG cells were more than 30 times more sensitive than EJ cells to SN-38G, showing that SN-38 could be generated from SN-38G in vitro. Systemic administration of CPT-11 resulted in tumor-located hydrolysis of SN-38G and accumulation of SN-38 in EJ/ mβG subcutaneous tumors. Importantly, systemic administration of CPT-11, which itself is not a substrate for β-glucuronidase, dramatically delayed the growth of EJ/ mβG xenografts without increased systemic toxicity. Thus, the anticancer activity of CPT-11 can be significantly enhanced by converting the relatively high levels of endogenously generated SN-38G to SN-38 in tumors. The high concentrations of SN-38G found in the serum of patients treated with CPT-11 suggest that clinical response to CPT-11 may be improved by elevating β-glucuronidase activity in tumors. [Mol Cancer Ther 2009;8(4):940-6]

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Tumor-targeting prodrug-activating bacteria for cancer therapy

Cited by 75 publications

References 38 publications

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

Bioluminescent Bacterial Imaging <em>In Vivo</em>

Local enzymatic hydrolysis of an endogenously generated metabolite can enhance CPT-11 anticancer efficacy

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