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Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes
Author(s) -
Altanerova Ursula,
Jakubechova Jana,
Benejova Katarina,
Priscakova Petra,
Pesta Martin,
Pitule Pavel,
Topolcan Ondrej,
Kausitz Juraj,
Zduriencikova Martina,
Repiska Vanda,
Altaner Cestmir
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31792
Subject(s) - microvesicles , suicide gene , cytosine deaminase , mesenchymal stem cell , cancer research , exosome , prodrug , biology , genetic enhancement , microrna , microbiology and biotechnology , gene , pharmacology , genetics
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.