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J Gene Med. 2008 Oct;10(10):1071-82. doi: 10.1002/jgm.1239.

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

Author information

1
Laboratories of Molecular Oncology, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia. exonkuce@savba.sk

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.

PMID:
18671316
DOI:
10.1002/jgm.1239
[Indexed for MEDLINE]

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