alexa Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice.


Journal of Clinical & Experimental Pathology

Author(s): Kucerova L, Matuskova M, Pastorakova A, Tyciakova S, Jakubikova J,

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Abstract BACKGROUND: Previously, we validated capability of human adipose tissue-derived mesenchymal stem cells (AT-MSC) to serve as cellular vehicles for gene-directed enzyme prodrug molecular chemotherapy. Yeast fusion cytosine deaminase : uracil phosphoribosyltransferase expressing AT-MSC (CD y-AT-MSC) combined with systemic 5-fluorocytosine (5FC) significantly inhibited growth of human colon cancer xenografts. We aimed to determine the cytotoxic efficiency to other tumour cells both in vitro and in vivo. METHODS: CD y-AT-MSC/5FC-mediated proliferation inhibition against a panel of human tumour cells lines was evaluated in direct and indirect cocultures in vitro. Antitumour effect was tested on immunodeficient mouse model in vivo. RESULTS: Although culture expansion of CD y-AT-MSC sensitized these cells to 5FC mediated suicide effect, expanded CD y-AT-MSC/5FC still exhibited strong bystander cytotoxic effect towards human melanoma, glioblastoma, colon, breast and bladder carcinoma in vitro. Most efficient inhibition (91\%) was observed in melanoma A375 cell line when directly cocultured with 2\% of therapeutic cells CD y-AT-MSC/5FC. The therapeutic paradigm of the CD y -AT-MSC/5FC system was further evaluated on melanoma A375 xenografts on nude mice in vivo. Complete regression in 89\% of tumours was achieved when 20\% CD y-AT-MSC/5FC were co-injected along with tumour cells. More importantly, systemic CD y-AT-MSC administration resulted in therapeutic cell homing into subcutaneous melanoma and mediated tumour growth inhibition. CONCLUSIONS: CD y-AT-MSC capability of targeting subcutaneous melanoma offers a possibility to selectively produce cytotoxic agent in situ. Our data further demonstrate beneficial biological properties of AT-MSC as a cellular vehicle for enzyme/prodrug therapy approach to molecular chemotherapy. Copyright (c) 2008 John Wiley & Sons, Ltd. This article was published in J Gene Med and referenced in Journal of Clinical & Experimental Pathology

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