Antibody-Directed Enzyme Prodrug Therapy

1995 ◽  
pp. 148-159
Author(s):  
Richard J. Knox
Keyword(s):  
Enzyme Prodrug Therapy

Microbial enzymes used in prodrug activation for cancer therapy: Insights and future perspectives

2020 ◽  
Vol 21 ◽  
Author(s):  
Rakhi Dhankhar ◽  
Anubhuti Kawatra ◽  
Aparajita Mohanty ◽  
Pooja Gulati
Keyword(s):  
Purine Nucleoside Phosphorylase ◽  
Cytosine Deaminase ◽  
Therapeutic Index ◽  
Enzyme Prodrug Therapy ◽  
Prodrug Activation ◽  
Microbial Enzymes ◽  
High Productivity ◽  
Delivery Vector ◽  
Exogenous Enzymes ◽  
Activation Therapy

Abstract:: Enzyme prodrug therapy has gained momentum in the recent years due to their ability to improve therapeutic index (benefits versus toxic side-effects) and efficacy of chemotherapy in cancer treatment. Inactive prodrugs used in this system are converted into active anti-cancerous drugs by enzymes, specifically within the tumor cells. This therapy involves three components namely prodrug, enzyme and gene delivery vector. Past reports have clearly indicated that the choice of enzyme used, is the major determinant for the success of this therapy. Generally, enzymes from non-human sources are employed to avoid off-target toxicity. Exogenous enzymes also give a better control to the clinician regarding the calibration of treatment by site-specific initiation. Amongst these exo-enzymes, microbial enzymes are preferred due to their high productivity, stability and ease of manipulation. The present review focuses on the commonly used microbial enzymes particularly cytosine deaminase, nitroreductase, carboxypeptidase, purine nucleoside phosphorylase in prodrug activation therapy. Various aspects viz. source of the enzymes, types of cancer targeted, mode of action and efficacy of the enzyme/prodrug system, efficient vectors used and recent research developments of each of these enzymes are comprehensively elaborated. Further, the results of the clinical trials and various strategies to improve their clinical applicability are also discussed.

scholarly journals Gene-Directed Enzyme Prodrug Therapy by Dendrimer-Like Mesoporous Silica Nanoparticles against Tumor Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1298
Author(s):  
Vicente Candela-Noguera ◽  
Gema Vivo-Llorca ◽  
Borja Díaz de Greñu ◽  
María Alfonso ◽  
Elena Aznar ◽  
...  
Keyword(s):  
Cell Death ◽  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Tumor Cells ◽  
Mesoporous Silica Nanoparticles ◽  
Combined Treatment ◽  
Bond Rupture ◽  
Enzyme Prodrug Therapy ◽  
Bacterial Gene ◽  
Reducing Environment

We report herein a gene-directed enzyme prodrug therapy (GDEPT) system using gated mesoporous silica nanoparticles (MSNs) in an attempt to combine the reduction of side effects characteristic of GDEPT with improved pharmacokinetics promoted by gated MSNs. The system consists of the transfection of cancer cells with a plasmid controlled by the cytomegalovirus promoter, which promotes β-galactosidase (β-gal) expression from the bacterial gene lacZ (CMV-lacZ). Moreover, dendrimer-like mesoporous silica nanoparticles (DMSNs) are loaded with the prodrug doxorubicin modified with a galactose unit through a self-immolative group (DOXO-Gal) and modified with a disulfide-containing polyethyleneglycol gatekeeper. Once in tumor cells, the reducing environment induces disulfide bond rupture in the gatekeeper with the subsequent DOXO-Gal delivery, which is enzymatically converted by β-gal into the cytotoxic doxorubicin drug, causing cell death. The combined treatment of the pair enzyme/DMSNs-prodrug are more effective in killing cells than the free prodrug DOXO-Gal alone in cells transfected with β-gal.

NIR‐II Absorbing Semiconducting Polymer‐Triggered Gene‐Directed Enzyme Prodrug Therapy for Cancer Treatment

Small ◽  
2021 ◽  
pp. 2100501
Author(s):  
Xun Zhang ◽  
Yanqing Yang ◽  
Tianyi Kang ◽  
Jun Wang ◽  
Guang Yang ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Enzyme Prodrug Therapy ◽  
Semiconducting Polymer

Next Generation of Antibody-Directed Enzyme Prodrug Therapy

2004 ◽  
Vol 27 (6) ◽  
pp. S53
Author(s):  
Judith Fox ◽  
Roanna Ueda ◽  
Douglas Hodges ◽  
Peter Yeung ◽  
Daniel Brigham ◽  
...  
Keyword(s):  
Next Generation ◽  
Enzyme Prodrug Therapy

Gene Directed Enzyme Prodrug Therapy for Ovarian Cancer: Could GDEPT Become a Promising Treatment Against Ovarian Cancer?

2008 ◽  
Vol 8 (2) ◽  
pp. 232-239 ◽  
Author(s):  
Akihiro Nawa ◽  
Tadatoshi Tanino ◽  
Chen Luo ◽  
Masahiro Iwaki ◽  
Hiroaki Kajiyama ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Enzyme Prodrug Therapy ◽  
Promising Treatment

scholarly journals Towards a ligand targeted enzyme prodrug therapy: Single round panning of a β-lactamase scaffold library on human cancer cells

2007 ◽  
Vol 120 (10) ◽  
pp. 2233-2242 ◽  
Author(s):  
Girja S. Shukla ◽  
Christopher J. Murray ◽  
Melodie Estabrook ◽  
Guang-Ping Shen ◽  
Volker Schellenberger ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Enzyme Prodrug Therapy ◽  
Human Cancer Cells

scholarly journals Coupling of a Novel TIMP3 Peptide to Carboxypeptidase G2 for Pro-Drug Activation at the Tumour Site

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 625
Author(s):  
Mohammed S. Aldughaim ◽  
Fatimah Alsaffar ◽  
Michael D. Barker
Keyword(s):  
Fold Increase ◽  
Repeated Administration ◽  
Cytotoxic Drugs ◽  
Peptide Sequence ◽  
Tumour Site ◽  
Enzyme Prodrug Therapy ◽  
Nickel Affinity Chromatography ◽  
Glutamic Acid Residue ◽  
Carboxypeptidase G2 ◽  
Effective Delivery

Broad-spectrum cytotoxic drugs have been used in cancer therapy for decades. However, their lack of specificity to cancer cells often results in serious side-effects, limiting efficacy. For this reason, antibodies have been used to attempt to specifically target cytotoxic drugs to tumours. One such approach is antibody-directed enzyme prodrug therapy (ADEPT) which uses a tumour-directed monoclonal antibody, coupled to an enzyme, to convert a systemically administered non-toxic prodrug into a toxic one only at the tumour site. Among the main drawbacks of ADEPT is the immunogenicity of the antibody-enzyme complex, which is exacerbated by slow clearance due to size, hence limiting repeated administration. Additionally, the mono-specificity of the antibody could potentially result in drug resistance with repeated administration. We have identified a novel short peptide sequence, p700, derived from a human tissue inhibitor of metalloproteinases-3 (TIMP-3), which binds to and inhibits a number of tyrosine kinase growth factor receptors (VEGFRs1-3, FGFRs 1-4 and PDGFRα) which are known to be upregulated in many tumours and tumour vasculature. In this report, we fused p700 to His-tagged, codon-optimised, carboxypeptidase G2 (CPG2). CPG2 is a bacterial enzyme used in ADEPT, which activates potent nitrogen-mustard pro-drugs by removal of an inhibitory glutamic acid residue. Recombinant CPG2-p700 was highly expressed in Escherichia coli and successfully purified by nickel affinity chromatography. Biolayer interferometry showed that CPG2-p700 had a 100-fold increase in binding affinity for VEGFR2 compared with CPG2 alone and retained its catalytic activity, as determined by methotrexate cleavage. In the presence of CPG2-p700, the ZD2676P pro-drug showed significant cytotoxicity for 4T1 cells compared with prodrug alone or CPG2 alone. p700 is, therefore, a potentially useful alternative to monoclonal antibodies for enzyme pro-drug therapy and could equally be used for effective delivery of other cytotoxic drugs to tumour tissue.

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

2018 ◽  
Vol 158 ◽  
pp. 192-200 ◽  
Author(s):  
Jasmine V.E. Chan-Hyams ◽  
Janine N. Copp ◽  
Jeff B. Smaill ◽  
Adam V. Patterson ◽  
David F. Ackerley
Keyword(s):  
Enzyme Prodrug Therapy ◽  
Gram Negative

Characterization of novel anthracycline prodrugs activated by human β-glucuronidase for use in antibody-directed enzyme prodrug therapy

1996 ◽  
Vol 52 (3) ◽  
pp. 455-463 ◽  
Author(s):  
Pieter H.J Houba ◽  
Ruben G.G Leenders ◽  
Epie Boven ◽  
Johannes W Scheeren ◽  
Herbert M Pinedo ◽  
...  
Keyword(s):  
Enzyme Prodrug Therapy
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