ArticleGene therapy2007
Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs.
Article in Gene therapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 19 citations in OpenAlex.
- Exploring the Mutated Kinases for Chemoenzymatic Synthesis ofMolecules (Basel, Switzerland) · 2024Article
- Recombinant deoxyribonucleoside kinase from Drosophila melanogaster can improve gemcitabine based combined gene/chemotherapy for targeting cancer cells.Bosnian journal of basic medical sciences · 2019Article
- New Variants of Tomato Thymidine Kinase 1 Selected for Increased Sensitivity of E. coli KY895 towards Azidothymidine.Cancers · 2015Article
- Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.Current gene therapy · 2012Review
- Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy.Neuro-oncology · 2010Article
- Directed evolution of an orthogonal nucleoside analog kinase via fluorescence-activated cell sorting.Nucleic acids research · 2009Article
- Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues.Cancer gene therapy · 2009Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Transduced deoxyribonucleoside kinases (dNK) can be used to kill recipient cells in combination with nucleoside prodrugs. The Drosophila melanogaster multisubstrate dNK (Dm-dNK) displays a superior turnover rate and has a great plasticity regarding its substrates. We used directed evolution to create Dm-dNK mutants with increased specificity for several nucleoside analogs (NAs) used as anticancer or antiviral drugs. Four mutants were characterized for the ability to sensitize Escherichia coli toward analogs and for their substrate specificity and kinetic parameters. The mutants had a reduced ability to phosphorylate pyrimidines, while the ability to phosphorylate purine analogs was relatively similar to the wild-type enzyme. We selected two mutants, for expression in the osteosarcoma 143B, the glioblastoma U-87M-G and the breast cancer MCF7 cell lines. The sensitivities of the transduced cell lines in the presence of the NAs fludarabine (F-AraA), cladribine (CdA), vidarabine and cytarabine were compared to the parental cell lines. The sensitivity of 143B cells was increased by 470-fold in the presence of CdA and of U-87M-G cells by 435-fold in the presence of F-AraA. We also show that a choice of the selection and screening system plays a crucial role when optimizing suicide genes by directed evolution.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.