Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice.
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.
Kucerova
Lucia
L
Laboratories of Molecular Oncology, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia. exonkuce@savba.sk
Matuskova
Miroslava
M
Pastorakova
Andrea
A
Tyciakova
Silvia
S
Jakubikova
Jana
J
Bohovic
Roman
R
Altanerova
Veronika
V
Altaner
Cestmir
C
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000818:Animals; D017209:Apoptosis; D019496:Cancer Vaccines / Q000235:genetics; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
D019496:Cancer Vaccines; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase