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Intrinsic properties of tumour cells have key impact on the bystander effect mediated by genetically engineered MSC.
MedLine Citation:
PMID:  23150190     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND: Engineered mesenchymal stromal cells (MSC) were used in many preclinical studies of gene directed enzyme/prodrug therapy. We aimed to compare the efficacy of two most frequently used systems, and evaluate extent of bystander effect mediated by therapeutic MSC towards cell lines derived from different tumours. METHODS: Two approaches were compared: (1.) Herpes simplex virus thymidine kinase (TK)/ganciclovir (GCV) and (2.) yeast cytosine deaminase fused with uracil phosphoribosyltransferase (CD::UPRT)/5-fluorocytosine (5-FC). Cytotoxic effect mediated by therapeutic MSC was evaluated in direct co-culture by fluorimetric assay. Expression profile of tumour cells was analysed by qPCR, and the ability of gap-junctional intercellular communication (GJIC) was evaluated by dye transfer assay. RESULTS: Both systems were effective only on glioblastoma cells (8-MB-BA). CD::UPRT-MSC/5-FC system showed efficiency on melanoma A375 cells. We decreased sensitivity of 8-MG-BA cells and A375 cells to CD::UPRT-MSC/5-FC system by pharmacologic inhibition of thymidylate synthase, and we achieved similar result in A375 cells by inhibition of thymidine phosphorylase. Although we demonstrated functional GJIC in A375 cells, TK-MSC were ineffective in mediating bystander effect similarly to HeLa cells, which were relatively resistant also to CD::UPRT-MSC/5-FC treatment. TK-MSC/GCV treatment had strong cytotoxic effect on MDA-MB-231 cells (breast carcinoma), but CD::UPRT-MSC/5-FC treatment failed due to overexpression of ABCC11 gene. Transfection of MDA-MB-231 cell line with small interference RNA specific to ABCC11 led to significantly increased sensitivity to CD::UPRT-MSC/5-FC approach. CONCLUSIONS: GJIC, expression of enzymes involved in drug metabolism and ABC transporters correlate with the response of tumour cells to treatment by MSC expressing prodrug-converting genes. Copyright © 2012 John Wiley & Sons, Ltd.
Authors:
Miroslava Matuskova; Lenka Baranovicova; Zuzana Kozovska; Erika Durinikova; Andrea Pastorakova; Lubica Hunakova; Iveta Waczulikova; Radim Nencka; Lucia Kucerova
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-13
Journal Detail:
Title:  The journal of gene medicine     Volume:  -     ISSN:  1521-2254     ISO Abbreviation:  J Gene Med     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815764     Medline TA:  J Gene Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 John Wiley & Sons, Ltd.
Affiliation:
Laboratory of Molecular Oncology, Cancer Research Institute of Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava, Slovakia. exonmigu@savba.sk.
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