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Prodrug Gene Therapy for Cancer Mediated by Mesenchymal Stem/Stromal Cells Engineered to Express Yeast Cytosinedeaminase::Uracilphos phoribosyltransferase

Cestmir Altaner

Prodrug cancer gene therapy mediated by human adipose tissue-derived mesenchymal stem/stromal cells (MSCs) engineered to express fused yeast cytosine deaminase::uracil phosphoribosyltransferase (Therapeutic Stem/Stromal Cells-ThSC) is an efficient experimental therapeutic modality for cancers. The attractiveness of prodrug cancer gene therapy by stem/stromal cells targeted to tumors lies in activating the nontoxic prodrug 5-fluorocytosine directly within the tumor mass to 5-fluorouracil, thus avoiding systemic toxicity. Prodrug administration not only eliminates tumor cells, but consequently kills the more resistant ThSC as well. The therapeutic potential of this system is universal and quite effective. In a series of papers, it was shown its effectiveness in targeting and killing human colorectal, melanoma, glioblastoma, colon, breast and bladder carcinoma cells both in vitro, and in vivo. Pilot preclinical studies demonstrated that intravenously administered ThSC were effective in significantly inhibiting subcutaneous xenografts bone metastatic prostate cells. Similar inhibiting effects were seen on spontaneous aggressive prostate adenocarcinoma on TRAMP mice. Complete tumor regression was observed in a rat glioblastoma intracerebral model. It is assumed that curative glioblastoma therapy is a consequence of elimination of glioma stem cells that drive the tumor progression. Both vector composition and unique properties of the vehicle stem/stromal cells contribute to high therapeutic efficiency. Mesenchymal stem/stromal cells transduced stably with yCD::UPRT gene produced exosomes. The exosomes upon easy internalization to tumor cells in the presence of 5-FC inhibit growth of a broad kind of cancer cells in vitro. The exosomes released from therapeutic stem/stromal cells significantly contribute to the therapeutic efficiency of the yCD::UPRT-MSCs/5-FC system. Results support arguments for beginning clinical studies for the treatment of high grade tumors and metastases.