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Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice
Author(s) -
Kucerova Lucia,
Matuskova Miroslava,
Pastorakova Andrea,
Tyciakova Silvia,
Jakubikova Jana,
Bohovic Roman,
Altanerova Veronika,
Altaner Cestmir
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1239
Subject(s) - cytosine deaminase , mesenchymal stem cell , cancer research , cytotoxic t cell , in vivo , melanoma , in vitro , chemistry , biology , genetic enhancement , microbiology and biotechnology , biochemistry , gene
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 CDy‐AT‐MSC/5FC. The therapeutic paradigm of the CDy‐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 © 2008 John Wiley & Sons, Ltd.