ArticleCancer research2009
Bacterial cytosine deaminase mutants created by molecular engineering show improved 5-fluorocytosine-mediated cell killing in vitro and in vivo.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 43 citations in OpenAlex.
- Engineered probiotics for tumor-targeted combination chemoimmunotherapy.Science translational medicine · 2026Article
- Programming tumor evolution with selection gene drives to proactively combat drug resistance.Nature biotechnology · 2025Article
- Mechanism of deamination by mycobacterial deaminase selectively targeting mutagenic bases.Nucleic acids research · 2025Article
- Review
- Enzyme Stabilization by Virus-Like Particles.Biochemistry · 2020Article
- Enzymes Photo-Cross-Linked to Live Cell Receptors Retain Activity and EGFR Inhibition after Both Internalization and Recycling.Bioconjugate chemistry · 2020Article
- Bacteria in Cancer Therapeutics: A Framework for Effective Therapeutic Bacterial Screening and Identification.Journal of Cancer · 2019Review
- Nucleobase deaminases: a potential enzyme system for new therapies.RSC advances · 2018Review
- Cytotoxic effect of co-expression of human hepatitis A virus 3C protease and bifunctional suicide protein FCU1 genes in a bicistronic vector.Molecular biology reports · 2017Article
- Progress and problems with the use of suicide genes for targeted cancer therapy.Advanced drug delivery reviews · 2016Review
- Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme-prodrug therapy.Journal of biotechnology · 2015Article
- Cytosine deaminase as a negative selectable marker for the microalgal chloroplast: a strategy for the isolation of nuclear mutations that affect chloroplast gene expression.The Plant journal : for cell and molecular biology · 2014Article
- Tumor-targeting bacterial therapy: A potential treatment for oral cancer (Review).Oncology letters · 2014Article
- Therapeutic potential of stem cells expressing suicide genes that selectively target human breast cancer cells: evidence that they exert tumoricidal effects via tumor tropism (review).International journal of oncology · 2012Review
- Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy.Current gene therapy · 2012Review
- Monitoring enzyme activity using a diamagnetic chemical exchange saturation transfer magnetic resonance imaging contrast agent.Journal of the American Chemical Society · 2011Article
- Comparative analysis of enzyme and pathway engineering strategies for 5FC-mediated suicide gene therapy applications.Cancer gene therapy · 2011Article
- Three-dimensional structure and catalytic mechanism of cytosine deaminase.Biochemistry · 2011Article
- Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β-glucuronidase in tumors.Cancer gene therapy · 2011Article
- HSV-TK/GCV cancer suicide gene therapy by a designed recombinant multifunctional vector.Nanomedicine : nanotechnology, biology, and medicine · 2011Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Cytosine deaminase is used in combination with 5-fluorocytosine as an enzyme-prodrug combination for targeted genetic cancer treatment. This approach is limited by inefficient gene delivery and poor prodrug conversion activities. Previously, we reported individual point mutations within the substrate binding pocket of bacterial cytosine deaminase (bCD) that result in marginal improvements in the ability to sensitize cells to 5-fluorocytosine (5FC). Here, we describe an expanded random mutagenesis and selection experiment that yielded enzyme variants, which provide significant improvement in prodrug sensitization. Three of these mutants were evaluated using enzyme kinetic analyses and then assayed in three cancer cell lines for 5FC sensitization, bystander effects, and formation of 5-fluorouracil metabolites. All variants displayed 18- to 19-fold shifts in substrate preference toward 5FC, a significant reduction in IC(50) values and improved bystander effect compared with wild-type bCD. In a xenograft tumor model, the best enzyme mutant was shown to prevent tumor growth at much lower doses of 5FC than is observed when tumor cells express wild-type bCD. Crystallographic analyses of this construct show the basis for improved activity toward 5FC, and also how two different mutagenesis strategies yield closely related but mutually exclusive mutations that each result in a significant alteration of enzyme specificity.
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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.