Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Kučerová, Lucia; Skolekova, Svetlana; Demkova, Lucia; Bohovic, Roman; Matúšková, Miroslava

doi:10.1038/gt.2014.66

Cited by 38 publications

(55 citation statements)

References 57 publications

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“…In order to diminish the viability to less than 90%, there had to be the 20% of the CD-MSC present at the culture initiation. This outcome corresponds to the data already published, when 20% of CD-MSC/5FC were able to significantly reduce the tumor growth and achieve a complete tumor regression in the 83.3% of the animals in a long-term experiment [12]. Although the 10% of the therapeutic cells significantly reduced a spheroid volume and achieved the 75% inhibition of the viability, this was sufficient for the tumor inhibition but not for the complete tumor eradication in animals.…”

Section: Discussionsupporting

confidence: 89%

“…Furthermore, the therapeutic-to-target cell ratio 1:20 CD-MSC/5FC:A375 decreased in vitro by 90% viability as determined by the standard MTS viability assay. These data correlated with the outcomes from the fluorimetric evaluation of the bystander effect and luminometric viability assay based on the ATP levels in the treated cells [12]. In contrast, it was necessary to co-inject 10% of therapeutic CD-MSC cells with the target melanoma A375 cells in order to achieve significant delay in the tumor onset.…”

supporting

confidence: 60%

“…By two independent methods we have seen that the multicellular nodules remained refractory to 5FU in vitro. This is in a sharp contrast to the sensitivity of A375 melanoma cells from the monolayer cultures to 5FU [12]. It is well established that melanoma cells are chemoresistant and do not respond to the chemotherapy in clinical situation in general, including 5FU-based regimens.…”

Section: Discussionmentioning

confidence: 81%

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3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Bohovic¹,

Demkova²,

Cihova³

et al. 2015

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Mesenchymal stromal cells (MSC) exhibit beneficial properties to serve as cellular vehicles for enzyme/prodrug cancer gene therapy approaches. We have previously shown that engineered human adipose tissue-derived MSC in combination with non-toxic prodrug mediated substantial cytotoxic and antitumor effect. The aim of this study was to develop advanced 3D cultivation method to serve for modelling of the therapeutic outcome in vitro. We have used engineered MSC expressing fusion transgene cytosine deaminase::uracilphosphoribosyltransferase (CD-MSC) in combination with prodrug 5-fluorocytosine (5FC). This therapeutic regimen designated CD-MSC/5FC was combined with the human melanoma cells A375 or EGFP-A375 in both standard monolayer culture and 3-dimensional (3D) multicellular nodules. The extent of cytotoxicity was evaluated by standard viability assay MTS, ATP-based luminescence assay, fluorimetric test, measurement of Caspase-3/7 activation and DNA laddering. The data have shown that the extent of cytotoxic bystander effect mediated by CD-MSC/5FC is significantly lower in 3D culture conditions. However, these data better recapitulate the therapeutic efficiency as observed previously in vivo. We suggest here to use the 3D multicellular culture conditions for better prediction of the therapeutic outcome in mouse xenograft models.

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Section: Discussionsupporting

confidence: 89%

supporting

confidence: 60%

Section: Discussionmentioning

confidence: 81%

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3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Bohovic¹,

Demkova²,

Cihova³

et al. 2015

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“…After systemic administration of therapeutic cells we observed signifi cant inhibition of growth of subcutaneous xenotransplants derived from colorectal cancer (12) or melanoma (13). In this melanoma model we also demonstrated that more than 80 % of treated mice survive for long-term without relapse (14).…”

Section: Gene Therapy Mediated By Mesenchymal Stromal Cellsmentioning

confidence: 75%

Genetically engineered mesenchymal stromal cells in cancer gene therapy

Matúšková¹,

Durinikova²,

Altaner³

et al. 2018

BLL

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Based on our experimental data, we aimed to emphasise the perspectives of the use of mesenchymal stromal cells (MSC) in the cancer gene therapy. On the other hand, we would like to point out factors which should be taken into consideration at their clinical use. In this review we defi ne MSC as unique targets for targeted therapy. We proved the effi cacy of experimental therapeutic approach utilising enzymatic conversion of non-toxic prodrug into chemotherapeutic by engineered MSC, and we observed signifi cant cytotoxic effect in many preclinical models including metastatic disease. Treatment was enabled by affi nity of MSC to tumour tissue and subsequent delivery of therapeutic molecule into the tumour. We also observed decreased effi cacy of cell-mediated gene therapy on chemoresistant tumour cells. Moreover MSC can exert a supportive effect on tumour cells as well as to decrease the effi cacy of conventional treatment. Besides obvious unique benefi ts connected to the use of MSC we pointed also to possible risks associated with their clinical application (Ref. 24). Text in PDF www.elis.sk.

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“…With the exception of gene therapy, 5-fluorocytosine (5-FC) and Na 131 I have also been used in cancer therapy combined with gene therapy: Kucerova et al (25) utilized CD-mesenchymal stromal cells/5-FC as an effective gene therapeutic tool. Zimmer et al (26) also used Na 131 I to mediate radiochemical therapy.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of adenovirus‑mediated CD and NIS expression combined with Na131I/5‑FC on human thyroid cancer

et al. 2017

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Abstract. Thyroid cancer is the most common type of malignant endocrine tumor diagnosed. Previous studies have indicated that gene therapy is the most promising and effective therapeutic method for thyroid cancer. Therefore, in the present study, Na 131 I/5-fluorocytosine (5-FC) treatment was combined with cytosine deaminase (CD, encoded by the CDA gene) and sodium iodide symporter (NIS, encoded by the SLC5A5 gene) to act together as a therapeutic tool for thyroid cancer. The present study explored the combined cytotoxic effects of adenovirus-mediated CD and NIS under the control of the progression elevated gene-3 (PEG-3) promoter (Ad-PEG-3-CD-NIS) with Na 131 I/5-FC against the human thyroid cancer TT cell line in vitro. The PEG-3 fragment was obtained by polymerase chain reaction (PCR) using rat genomic DNA as the template, and then Ad-PEG-3-CDA-SLC5A5 was constructed using XbaI. TT cells were transfected by recombinant adenovirus. The method of reverse transcription-quantitative PCR was performed to test the expression of CD and NIS at the level of transcription. The morphological change was assessed by fluorescence microscopy and investigated by western blot analysis. An MTT assay was used to determine the number of living cells inhibited by single or combination therapies on TT cells. The results indicated that the PEG-3 was successfully cloned, and was also positively regulated in 293 cells. CDA and SLC5A5 genes were highly expressed in TT cells. Na 131 I combined with 5-FC significantly decreased the human thyroid cancer cells. In conclusion, combination therapy of Ad-PEG3-CDA-SLC5A5 and Na 131 I/5-FC induces significantly more apoptotic characteristics than either single treatment with Ad-PEG-3-CDA-SLC5A5 or Na 131 I/5-FC, and low doses of Ad-PEG-3-CDA-SLC5A5 enhanced the cytotoxic effects.

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Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

Cited by 38 publications

References 57 publications

3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

3D multicellular models reflect the efficiency of MSC-directed enzyme/prodrug treatment

Genetically engineered mesenchymal stromal cells in cancer gene therapy

Therapeutic effects of adenovirus‑mediated CD and NIS expression combined with Na131I/5‑FC on human thyroid cancer

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