Designer bacteria as intratumoural enzyme biofactories

Lehouritis, Panos; Hogan, Glenn; Tangney, Mark

doi:10.1016/j.addr.2017.09.012

Cited by 19 publications

(13 citation statements)

References 167 publications

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“…The design of the BDEPT system is critical and factors such as enzyme orientations, enzyme kinetics, toxicity of the prodrug/active pharmaceutical ingredient to the bacterium, and pharmacokinetic properties of the drug should be considered. Selection of an appropriate bacterial carrier is vital considering the level of invasiveness—intracellular or extracellular, wild type or recombinant carrier, and nature of the bacterium—facultative or obligate anaerobic bacteria [ 78 ].…”

Section: Mechanism Of Tumor Suppressionmentioning

confidence: 99%

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

Sawant

Patil

Gupta

et al. 2020

IJMS

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Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.

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Section: Mechanism Of Tumor Suppressionmentioning

confidence: 99%

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

Sawant

Patil

Gupta

et al. 2020

IJMS

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“…For centuries, food processing and fermentation industries have driven the commercial markets of bacterial based products. The advent of recombinant technology paved the way for various engineered enzymes and novel protein-based therapeutics [2]- [4]. In all those mentioned above, clinical, scientific, and commercial settings, monitoring of the population, and growth kinetics of bacteria plays a crucial role [5], [6].…”

Section: Introductionmentioning

confidence: 99%

ODX: A Fitness Tracker-Based Device for Continuous Bacterial Growth Monitoring

et al. 2019

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Continuous monitoring of bacterial growth in aqueous media is a crucial process in academic research as well as in the biotechnology industry. Bacterial growth is usually monitored by measuring the optical density of bacteria in liquid media, using benchtop spectrophotometers. Due to the large form factor of the existing spectrophotometers, they cannot be used for live monitoring of the bacteria inside bacterial incubation chambers. Additionally, the use of benchtop spectrometers for continuous monitoring requires multiple samplings and is labour intensive. To overcome these challenges, we have developed an optical density measuring device (ODX) by modifying a generic fitness tracker. The resulting ODX device is an ultra-portable and low-cost device that can be used inside bacterial incubators for real-time monitoring even while shaking is in progress. We evaluated the performance of ODX with different bacterial types and growth conditions and compared it with a commercial benchtop spectrophotometer. In all cases, ODX showed comparable performance to that of the standard benchtop spectrophotometer. Finally, we demonstrate a simple and useful smartphone application whereby the user is notified Page 1 of 18 ACS Paragon Plus Environment Analytical Chemistry when the bacterial concentration reaches the targeted value. Due to its potential for automation and mass production, we believe that the ODX has a wide range of applications in biotechnology research and industry.

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“…Bacteria offer several advantages as vectors for cancer gene therapy. For example, bacteria are easily manipulated to generate exogenous products of therapeutic relevance, to improve their tumour selectivity, or to express prodrug activating enzymes and reporter proteins for visual confirmation of treatment location and therapeutic outcome [11,17,9]. Different types of bacteria have different mechanisms of achieving tumour specificity.…”

Section: Introductionmentioning

confidence: 99%

“…Obligate anaerobes such as Gram-positive Clostridium species can form spores that are only able to germinate inside the anoxic regions of tumours [20]. In contrast, facultative anaerobes, such as Gram-negative Salmonella and Escherichia, accumulate inside tumours for several reasons: protection from the immune system, positive chemotaxis towards resources inside the tumour micro-environment and entrapment in the chaotic vasculature of tumours [11,17,9]. Bacteria offer one additional key advantage over their viral vector counterpartsbacterial infection during cancer therapy can readily be controlled by antibiotics [11,20,17].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model Gram negative vector for bacterial-directed enzyme-prodrug therapy

Chan-Hyams

Copp

Smaill

et al. 2018

Biochemical Pharmacology

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Gene-directed enzyme-prodrug therapy (GDEPT) employs tumour-tropic vectors including viruses and bacteria to deliver a genetically-encoded prodrug-converting enzyme to the tumour environment, thereby sensitising the tumour to the prodrug. Nitroreductases, able to activate a range of promising nitroaromatic prodrugs to genotoxic metabolites, are of great interest for GDEPT. The bystander effect (cell-to-cell transfer of activated prodrug metabolites) has been quantified for some nitroaromatic prodrugs in mixed multilayer human cell cultures, however while these provide a good model for viral DEPT (VDEPT) they do not inform on the ability of these prodrug metabolites to exit bacterial vectors (relevant to bacterial-DEPT (BDEPT)). To investigate this we grew two Escherichia coli strains in co-culture; an activator strain expressing the nitroreductase E. coli NfsA and a recipient strain containing an SOS-GFP DNA damage responsive gene construct. In this system, induction of GFP by reduced prodrug metabolites can only occur following their transfer from the activator to the recipient cells. We used this to investigate five clinically relevant prodrugs: metronidazole, CB1954, nitro-CBI-DEI, and two dinitrobenzamide mustard prodrug analogues, PR-104A and SN27686. Consistent with the bystander efficiencies previously measured in human cell multilayers, reduced metronidazole exhibited little bacterial cell-to-cell transfer, whereas nitro-CBI-DEI was passed very efficiently from activator to recipient cells post-reduction. However, in contrast with observations in human cell multilayers, the nitrogen mustard prodrug metabolites were not effectively passed between the two bacterial strains, whereas reduced CB1954 was transferred efficiently. Using nitroreductase enzymes that exhibit different biases for the 2-versus 4-nitro substituents of CB1954, we further showed that the 2-nitro reduction products exhibit substantially higher levels of bacterial cell-to-cell transfer than the 4-nitro reduction products, consistent with their relative bystander efficiencies in human cell culture. Overall, our data suggest that prodrugs may differ in their suitability for VDEPT versus BDEPT applications and emphasise the importance of evaluating an enzyme-prodrug partnership in an appropriate context for the intended vector.

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Designer bacteria as intratumoural enzyme biofactories

Cited by 19 publications

References 167 publications

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

ODX: A Fitness Tracker-Based Device for Continuous Bacterial Growth Monitoring

Evaluating the abilities of diverse nitroaromatic prodrug metabolites to exit a model Gram negative vector for bacterial-directed enzyme-prodrug therapy

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