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Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes
U. Altanerova, J. Jakubechova, K. Benejova, P. Priscakova, M. Pesta, P. Pitule, O. Topolcan, J. Kausitz, M. Zduriencikova, V. Repiska, C. Altaner,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
30098225
DOI
10.1002/ijc.31792
Knihovny.cz E-resources
- MeSH
- Cytosine Deaminase genetics metabolism MeSH
- Exosomes genetics metabolism MeSH
- Flucytosine metabolism MeSH
- Fluorouracil metabolism pharmacology MeSH
- Fungal Proteins genetics metabolism MeSH
- Genetic Therapy methods MeSH
- Yeasts genetics metabolism MeSH
- Humans MeSH
- Mesenchymal Stem Cells metabolism MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms genetics metabolism pathology MeSH
- Pentosyltransferases genetics metabolism MeSH
- Prodrugs metabolism MeSH
- Cell Proliferation drug effects genetics MeSH
- Antimetabolites, Antineoplastic metabolism pharmacology MeSH
- Genes, Transgenic, Suicide genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
Cancer Research Institute Biomedical Center Slovak Academy of Sciences Bratislava Slovakia
St Elisabeth Cancer Institute Stem Cell Preparation Department Bratislava Slovakia
References provided by Crossref.org
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- $a The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
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