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Caroline J. Springer - One of the best experts on this subject based on the ideXlab platform.

  • Bacterial-directed Enzyme Prodrug Therapy.
    Journal of controlled release : official journal of the Controlled Release Society, 2013
    Co-Authors: Panos Lehouritis, Caroline J. Springer, Mark Tangney
    Abstract:

    Abstract Current conventional treatments for cancer lack tumour selectivity resulting in the destruction of healthy tissue and severe adverse effects to the patient in addition to limiting the administration dose and efficacy. Hence, it is imperative that we seek alternative approaches to treat cancer that localise therapeutic agents to the site of the tumour and spare normal tissue. The use of bacteria in cancer Therapy represents one such approach. Bacteria were first used as anti-cancer agents over a century ago. Today, this field has re-emerged from the past and is progressing at a rapid rate. Bacteria are used as anticancer agents either alone or in combination with conventional treatments and have been armed with an arsenal of therapeutic genes, which enhance their efficacy. Bacterial directed Enzyme Prodrug Therapy (BDEPT) is one of the most promising approaches, which harnesses the tumour-specific location of bacteria to locally activate systemically administered ‘Prodrugs’ within the tumour in order to induce selective tumour destruction. BDEPT is a relatively new concept. It was originally conceived more than 10 years ago but it is only until recently that we witness a surge in activity in this field. In this review, we provide a full account of developments in the field of BDEPT since its inception. We share technical knowhow and discuss optimization strategies for vector and Enzyme combinations, provide a clear view of the research landscape and suggest possible directions for the field.

  • carboxypeptidase g2 based gene directed Enzyme Prodrug Therapy a new weapon in the gdept armoury
    Nature Reviews Cancer, 2007
    Co-Authors: Douglas Hedley, Lesley Ogilvie, Caroline J. Springer
    Abstract:

    Gene-directed Enzyme-Prodrug Therapy (GDEPT) aims to improve the therapeutic ratio (benefit versus toxic side-effects) of cancer chemoTherapy. A gene encoding a 'suicide' Enzyme is introduced into the tumour to convert a subsequently administered non-toxic Prodrug into an active drug selectively in the tumour, but not in normal tissues. Significant effects can now be achieved in vitro and in targeted experimental models, and GDEPT therapies are entering the clinic. Our group has developed a GDEPT system that uses the bacterial Enzyme carboxypeptidase G2 to convert nitrogen mustard Prodrugs into potent DNA crosslinking agents, and a clinical trial of this system is pending.

  • carboxypeptidase g2 based gene directed Enzyme Prodrug Therapy a new weapon in the gdept armoury
    Nature Reviews Cancer, 2007
    Co-Authors: Douglas Hedley, Lesley Ogilvie, Caroline J. Springer
    Abstract:

    Gene-directed Enzyme–Prodrug Therapy (GDEPT) aims to improve the therapeutic ratio by increasing tumour cell kill and decreasing systemic toxicity. How is this achieved and how close is this Therapy to entering the clinic?

  • Carboxypeptidase G2-based gene-directed Enzyme–Prodrug Therapy: a new weapon in the GDEPT armoury
    Nature Reviews Cancer, 2007
    Co-Authors: Douglas Hedley, Lesley Ogilvie, Caroline J. Springer
    Abstract:

    Gene-directed Enzyme–Prodrug Therapy (GDEPT) aims to improve the therapeutic ratio by increasing tumour cell kill and decreasing systemic toxicity. How is this achieved and how close is this Therapy to entering the clinic?

  • Carboxypeptidase G2-based gene-directed Enzyme–Prodrug Therapy: a new weapon in the GDEPT armoury
    Nature reviews. Cancer, 2007
    Co-Authors: Douglas Hedley, Lesley Ogilvie, Caroline J. Springer
    Abstract:

    Gene-directed Enzyme-Prodrug Therapy (GDEPT) aims to improve the therapeutic ratio (benefit versus toxic side-effects) of cancer chemoTherapy. A gene encoding a 'suicide' Enzyme is introduced into the tumour to convert a subsequently administered non-toxic Prodrug into an active drug selectively in the tumour, but not in normal tissues. Significant effects can now be achieved in vitro and in targeted experimental models, and GDEPT therapies are entering the clinic. Our group has developed a GDEPT system that uses the bacterial Enzyme carboxypeptidase G2 to convert nitrogen mustard Prodrugs into potent DNA crosslinking agents, and a clinical trial of this system is pending.

William A. Denny - One of the best experts on this subject based on the ideXlab platform.

Kenneth D. Bagshawe - One of the best experts on this subject based on the ideXlab platform.

  • Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and tribulations.
    Advanced drug delivery reviews, 2017
    Co-Authors: Surinder K. Sharma, Kenneth D. Bagshawe
    Abstract:

    Antibody directed Enzyme Prodrug Therapy has the potential to be an effective Therapy for most common solid cancers. Clinical studies with CPG2 system have shown the feasibility of this approach. The key limitation has been immunogenicity of the Enzyme. Technologies now exist to eliminate this problem. Non-immunogenic Enzymes in combination with Prodrugs that generate potent cytotoxic drugs can provide a powerful approach to cancer Therapy. ADEPT has the potential to be non -toxic to normal tissue and can therefore be combined with other modalities including immunoTherapy for greater clinical benefit.

  • Translating antibody directed Enzyme Prodrug Therapy (ADEPT) and prospects for combination.
    Expert opinion on biological therapy, 2016
    Co-Authors: Surinder K. Sharma, Kenneth D. Bagshawe
    Abstract:

    ABSTRACTIntroduction: The generation of cytotoxic drugs, selectively within tumours, from non-toxic Prodrugs by targeted Enzymes provides a powerful system for cancer Therapy. In the form of Antibody directed Enzyme Prodrug Therapy (ADEPT), this approach has shown feasibility in the clinic.Areas covered: Although numerous Enzyme Prodrug combinations have been reported over the last two decades, only the CPG2 ADEPT system has progressed to clinical trials. Using readily available components such as chemical antibody Enzyme conjugate or recombinant multifunctional fusion protein, delivery of a specific Enzyme to tumours, its elimination from non-tumour sites and Prodrug activation has been achieved with therapeutic benefit in the clinic. The challenge here is to overcome immunogenicity of CPG2. Technology exists to overcome this limitation together with prospects for rational design of combined Therapy.Expert opinion: ADEPT has the potential to be an effective treatment for solid cancer. However, the system...

  • Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
    2014
    Co-Authors: Surinder K. Sharma, Kerry A. Chester, Kenneth D. Bagshawe
    Abstract:

    © 2014 Wiley-VCH Verlag GmbH & Co. KGaA. All rights reserved. Antibody-directed Enzyme Prodrug Therapy (ADEPT) was designed to generate high concentration of a cytotoxic agent selectively within tumors. Preclinical studies and clinical trials have improved our knowledge of the essential requirements for a successful ADEPT system. As a potential nontoxic Therapy, ADEPT may be developed as a combined Therapy with other clinically useful agents.

  • Antibody directed Enzyme Prodrug Therapy (ADEPT)
    2009
    Co-Authors: Helen Lowe, Kenneth D. Bagshawe, Surinder K. Sharma, Kerry A. Chester
    Abstract:

    © Cambridge University Press, 2009.In antibody-directed Enzyme Prodrug Therapy (ADEPT), an antibody is used to target an Enzyme to tumor. After tumor localization and deactivation or clearance of Enzyme from blood and other normal tissue, a Prodrug is given. The Prodrug is converted into a toxic chemotherapeutic by the pretargeted Enzyme at the tumor site (Figure 22.1). The ADEPT system, originally conceived in 1987, has a number of potential advantages over standard chemoTherapy or the use of antibody-toxin conjugates. If a relatively nontoxic Prodrug is used and there is no significant conversion of Prodrug in nontarget organs, toxicity is restricted to the tumor site, allowing highly potent and specific treatments. Moreover, since one Enzyme is able to turn over many Prodrug molecules, the tumor essentially becomes a factory for generating its own means of destruction. Importantly, active drug can also diffuse to nearby cells, creating a local bystander effect where antigen negative cells and tumor-supportive stromal elements are destroyed. ADEPT is a complex system that can be influenced by many components. These components, outlined inFigure 22.2, have been investigated by various workers over the last 2 decades and the results provide a platform of understanding for future applications of the treatment. Here we describe the progress of ADEPT since the first proofs-of-principle to recent advances in the clinic.

  • Antibody-Directed Enzyme Prodrug Therapy (ADEPT) for Cancer
    Expert review of anticancer therapy, 2006
    Co-Authors: Kenneth D. Bagshawe
    Abstract:

    Antibody-directed Enzyme Prodrug Therapy (ADEPT) is a system that aims to restrict the action of a high concentration of a cytotoxic drug to cancer sites. This is achieved by using an antibody (or antibody fragment) to deliver a non-human Enzyme to cancer sites.

Roger G. Harrison - One of the best experts on this subject based on the ideXlab platform.

  • Antitumor activity of an Enzyme Prodrug Therapy targeted to the breast tumor vasculature.
    Cancer investigation, 2013
    Co-Authors: Brent D. Van Rite, John J. Krais, Mohamad Cherry, Vassilios I. Sikavitsas, Carla Kurkjian, Roger G. Harrison
    Abstract:

    The L-methioninase-annexin V/selenomethionine Enzyme Prodrug system, designed to target the tumor vasculature and release the methylselenol anticancer drug in the tumor, was tested in mice with implanted MBA-MB-231 breast tumors. This Therapy was able to cause a reduction in the size of the tumors during the treatment period. It was shown that L-methioninase-annexin V was uniformly bound at the blood vessel surface in the tumor and also that there was a substantial cutoff of blood flowing through the treated tumor, consistent with the Therapy's design. This new approach for Enzyme Prodrug Therapy of breast cancer appears promising.

  • annexin v targeted Enzyme Prodrug Therapy using cytosine deaminase in combination with 5 fluorocytosine
    Cancer Letters, 2011
    Co-Authors: Brent D. Van Rite, Roger G. Harrison
    Abstract:

    A fusion protein, consisting of cytosine deaminase (CD) linked to human annexin V, was created for use in an Enzyme Prodrug Therapy targeted to the tumor vasculature and associated cancer cells in the primary tumor and distant metastases. The major finding of this study is that the CD-annexin V fusion protein in combination with the Prodrug 5-fluorocytosine has significant cytotoxic activity against endothelial cells and two breast cancer cells lines in vitro that expose phosphatidylserine on their surface. The cytotoxicity experiments verified this novel Enzyme Prodrug system has the ability to produce therapeutic levels of 5-fluorouracil and thus appears promising.

  • Enzyme Prodrug Therapy designed to target L-methioninase to the tumor vasculature.
    Cancer letters, 2010
    Co-Authors: Brent D. Van Rite, Yahya A. Lazrak, Magali L. Pagnon, Naveen R. Palwai, Luis F F Neves, Peter S. Mcfetridge, Roger G. Harrison
    Abstract:

    A new approach for Enzyme Prodrug Therapy for cancer was tested using human endothelial cells and two breast cancer cell lines in vitro. The concept is to use the human annexin V protein to selectively target the Enzyme L-methioninase to the tumor vasculature. The major finding was that Enzyme Prodrug treatment using the L-methioninase-annexin V fusion protein and selenomethionine as the Prodrug over 3 days was shown to be lethal to the endothelial cells and the cancer cells, while having little or no effect with the Prodrug but with no fusion protein present. Thus, this new approach appears promising.

Peter F Searle - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of NF-κB enhances the cytotoxicity of virus-directed Enzyme Prodrug Therapy and oncolytic adenovirus cancer gene Therapy
    Gene therapy, 2005
    Co-Authors: Daniel H. Palmer, David J. Kerr, Peter F Searle, Ming-jen Chen, Lawrence S Young
    Abstract:

    Virus-directed Enzyme Prodrug Therapy utilizing the bacterial Enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the Prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. Similarly, selectively replicating oncolytic adenoviruses are entering clinical trials. An understanding of interactions between vector and target cell are critical to the development of these strategies. We demonstrate that adenovirus vectors activate cellular pathways that promote cell survival in an NF-kB-dependent manner, and consequently have a negative effect on the efficacy of cell killing induced by cancer gene Therapy strategies. This provides a potential therapeutic target to enhance the cytotoxicity of these approaches.

  • Virus-directed Enzyme Prodrug Therapy using CB1954.
    Anti-cancer drug design, 1999
    Co-Authors: Jane I. Grove, Iain A Mcneish, N K Green, Peter F Searle, S. J. Weedon, David J. Kerr
    Abstract:

    The virus-directed Enzyme Prodrug Therapy (VDEPT) anti-cancer 'gene Therapy' strategy relies on the use of viral vectors for the efficient delivery to tumour cells of a 'suicide gene' encoding an Enzyme which converts a non-toxic Prodrug to a cytotoxic agent. The Prodrug 5-(aziridin-1-yl)-2,4 dinitrobenzamide, CB1954, has been proposed for use in Enzyme-Prodrug gene Therapy systems with the Escherichia coli Enzyme nitroreductase (Ntr). Ntr converts CB1954 to 2- and 4-hydroxylamino derivatives, whereupon the non-enzymatic reaction of the 4-hydroxylamino derivative with cellular thio- esters generates a potent cytotoxic bifunctional alkylating agent capable of cross-linking DNA. Ntr delivery has been achieved in vitro using retroviral and adenoviral vectors and confirmed by immunocytochemical demonstration of Ntr expression. The Ntr-expressing cells have been shown to be sensitized to CB1954 by up to 2000-fold. The Ntr-CB1954 system shows effective bystander killing in mixed populations of Ntr-expressing and non-expressing cells treated with CB1954. The efficacy of this Enzyme-Prodrug approach in model systems compared with other VDEPT approaches demonstrates the feasibility and future promise of this gene Therapy strategy.

  • virus directed Enzyme Prodrug Therapy for ovarian and pancreatic cancer using retrovirally delivered e coli nitroreductase and cb1954
    Gene Therapy, 1998
    Co-Authors: Iain A Mcneish, N K Green, Moira G Gilligan, M J Ford, Vivien Mautner, Lawrence S Young, D J Kerr, Peter F Searle
    Abstract:

    Virus directed Enzyme Prodrug Therapy for ovarian and pancreatic cancer using retrovirally delivered E. coli nitroreductase and CB1954

  • Gene directed Enzyme Prodrug Therapy for cancer.
    Advanced Drug Delivery Reviews, 1997
    Co-Authors: Iain A Mcneish, Lawrence S Young, Peter F Searle, David J. Kerr
    Abstract:

    One strategy for gene Therapy in malignant disease is gene directed Enzyme Prodrug Therapy (GDEPT). An exogenous Enzyme gene is delivered to tumour cells. The Enzyme, when expressed, can convert a non-toxic Prodrug into a cytotoxic species that is capable of killing the cell in which it has been produced. The most frequently used systems are HSV thymidine kinase with ganciclovir and E. coli cytosine deaminase with 5-fluorocytosine. The bystander effect is of key importance to GDEPT: This describes the local spread of active species from cells that express the Enzyme to kill adjacent, untransduced cells. The ultimate success of GDEPT will depend on the ability to achieve efficient gene delivery to and expression in target cells, whilst minimising expression in other tissues. A variety of techniques exist to achieve this goal, including loco-regional administration, manipulation of tumour blood supply and use of tumour-specific promoters to drive Enzyme gene expression.