Abstract
BackgroundMetastatic spread of tumor cells remains a serious problem in cancer treatment. Gene-directed enzyme/prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. Efficacy of gene-directed enzyme/prodrug therapy can be improved by combination of individual systems. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP.MethodsHuman adipose tissue-derived mesenchymal stromal cells (AT-MSC) were retrovirally transduced with fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT) or with Herpes simplex virus thymidine kinase (HSVtk). Engineered MSC were cocultured with tumor cells in the presence of prodrugs 5-fluorocytosin (5-FC) and ganciclovir (GCV). Combination effect of these enzyme/prodrug approaches was calculated. SCID/bg mice bearing experimental lung metastases were treated with CD::UPRT-MSC, HSVtk-MSC or both in combination in the presence of respective prodrug(s). Treatment efficiency was evaluated by EGFP-positive cell detection by flow cytometry combined with real-time PCR quantification of human cells in mouse organs. Results were confirmed by histological and immunohistochemical examination.ResultsWe demonstrated various extent of synergy depending on tested cell line and experimental setup. The strongest synergism was observed on breast cancer-derived cell line MDA-MB-231/EGFP. Systemic administration of CD::UPRT-MSC and HSVtk-MSC in combination with 5-FC and GCV inhibited growth of MDA-MB-231 induced lung metastases.ConclusionsCombined gene-directed enzyme/prodrug therapy mediated by MSC exerted synergic cytotoxic effect and resulted in high therapeutic efficacy in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0149-2) contains supplementary material, which is available to authorized users.
Highlights
Mesenchymal stromal cells (MSC) possess the tumorhoming capability which predetermines them as suitable vehicles for delivery of therapeutic molecules into sites of tumor burden [1,2,3]
We have demonstrated insufficient efficacy of the treatment by adipose tissue-derived mesenchymal stromal cells (MSC) (AT-MSC) expressing cytosine deaminase (CD)::UPRT combined with 5-FC on adenocarcinoma-derived cell line MDA-MB-231/enhanced green fluorescent protein (EGFP) in vitro
We demonstrated synergy of the combined MSC-based gene therapy and significant therapeutic effect on experimental lung metastases induced by MDA-MB-231/EGFP cell line
Summary
Mesenchymal stromal cells (MSC) possess the tumorhoming capability which predetermines them as suitable vehicles for delivery of therapeutic molecules into sites of tumor burden [1,2,3]. Systemic administration of MSC expressing prodrug-converting gene in combination with appropriate prodrug represents one of the promising experimental approaches in cancer treatment. It was demonstrated on glioblastoma, melanoma, prostate, colon and hepatocellular carcinoma model [4,5,6,7]. Gene-directed enzyme/ prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP
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