A specific subpopulation of mesenchymal stromal cell carriers overrides melanoma resistance to an oncolytic adenovirus.

The homing properties of mesenchymal stromal cells (MSCs) toward tumors turn them into attractive tools for combining cell and gene therapy. The aim of this study was to select in a feasible way a human bone marrow-derived MSC subpopulation that might exhibit a selective ability to target the tumor mass. Using differential in vitro adhesive capacities during cells isolation, we selected a specific MSC subpopulation (termed MO-MSCs) that exhibited enhanced multipotent capacity and increased cell surface expression of specific integrins (integrins α2, α3, and α5), which correlated with an enhanced MO-MSCs adhesiveness toward their specific ligands. Moreover, MO-MSCs exhibited a higher migration toward conditioned media from different cancer cell lines and fresh human breast cancer samples in the presence or not of a human microendothelium monolayer. Further in vivo studies demonstrated increased tumor homing of MO-MSCs toward established 578T and MD-MBA-231 breast cancer and A375N melanoma tumor xenografts. Tumor penetration by MO-MSCs was highly dependent on metallopeptidases production as it was inhibited by the specific inhibitor 1,10 phenantroline. Finally, systemically administered MO-MSCs preloaded with an oncolytic adenovirus significantly inhibited tumor growth in mice harboring established A375N melanomas, overcoming the natural resistance of the tumor to in situ administration of the oncolytic adenovirus. In summary, this work characterizes a novel MSC subpopulation with increased tumor homing capacity that can be used to transport therapeutic compounds.

Effect of dithiocarbamate pesticide zineb and its commercial formulation, azzurro. III. Genotoxic evaluation on Chinese hamster ovary (CHO) cells.

The in vitro genotoxicity exerted by the dithiocarbamate fungicide zineb, and its commercial formulation azzurro, were studied in Chinese hamster ovary (CHO) cells by the analysis of the sister chromatid exchange (SCE), cell-cycle progression and single cell gel electrophoresis (SCGE) assays. Both zineb and azzurro activities were tested within the range of 0.1-100.0 microg/ml. Concentrations of 0.1-25.0 microg/ml of zineb or azzurro induced a significant dose-dependent increase in SCE frequency over control values. For both test compounds, while doses ranging from 0.1 to 1.0 microg/ml did not alter the rate of cell proliferation, a significant delay in cell-cycle progression was observed within the 5.0-25.0 microg/ml dose-range. A regression test showed that either the proliferative replication index or the mitotic activity of cultures decreased as a function of the pesticide concentration within the 1.0-25.0 microg/ml dose-range. Doses higher than 50.0 microg/ml were cytotoxic. SCGE assay revealed an increase in zineb-induced DNA damage by enhancing the proportion of slightly damaged cells in the 25.0-100.0 microg/ml dose-range and by increasing in a dose-dependent manner the proportion of damaged cells within the 1.0-100.0 microg/ml dose-range. Overall, image analysis showed statistically significant positive relationships between zineb concentration and DNA damage (expressed by image length and width) and between length and width of the damaged cells. In azzurro-treated cells, only when 100.00 microg/ml was employed a significant increase in the frequency of damaged cells over control values affecting the totality of the cells was observed only when 100.0 microg/ml was employed. When lower doses were employed, no DNA damage was revealed. Based on these results, the evaluation of zineb as a genotoxic/non-genotoxic compound for human health should be reconsidered. Even though we demonstrate that the pesticide induces large DNA alterations in vitro, does no necessarily mean that the chemical should be considered clastogenic.notoxic