| http://purl.uniprot.org/citations/33504102 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/33504102 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.org/dc/terms/identifier | "doi:10.3390/molecules26030625"xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/author | "Barker M.D."xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/author | "Aldughaim M.S."xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/author | "Alsaffar F."xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/date | "2021"xsd:gYear |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/name | "Molecules"xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/pages | "625"xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/title | "Coupling of a Novel TIMP3 Peptide to Carboxypeptidase G2 for Pro-Drug Activation at the Tumour Site."xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://purl.uniprot.org/core/volume | "26"xsd:string |
| http://purl.uniprot.org/citations/33504102 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/33504102 |
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