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Randomized experimental treatment for colorectal cancer using an endoscopic device in combination with bleomycin or saline.

ABSTRACT: Primary objectives: The aim of this randomized trial, is to establish thesafety and efficacy of electrochemotherapy in patients with colorectalcancer, as an additive treatment prior to intended curative surgery. Theelectroporation regime in this trial will be delivered through andendoscopic device, EndoVE. The CliniporatorTM will be used for pulsegeneration Primary endpoints: To investigate if electrochemotherapy is an efficient treatment modality for tumor down staging compared with electroporation alone prior to intended curative surgery in patients undergoing treatment for colorectal cancer.

DISEASE(S): Colorectal Cancer

PROVIDER: 2540004 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:In this project we aimed at deciphering modulation in genes expression induced by external pulsed electric fields applied in reversible electroporation-based treatments. Thanks to their local application and transient effects, physical stimuli appear as attractive tools to remodel extracellular matrix, which was the point of interest in our to be published study. We assessed the potential of pulsed electric field technology, classically applied to drug delivery, to induce collagen remodeling at the tissue scale. A sophisticated in vitro tissue-engineered human dermal substitute, a tissue model rich in endogeneous extracellular matrix such as collagens, was used to demonstrate the effects of microsecond and millisecond pulsed electric fields applied respectively in electrochemotherapy (ECT) treatment and gene electrotransfer (GET) strategy. Our analyses, focused on matrisome genes and extracellular matrix remodeling, underpin that pulsed electric fields, a technology already approved for clinical use combined with anti-cancer agents, are particularly promising to provide local and effective treatment of abnormal extracellular matrix. Part of this dataset was used to describe how pulsed electric field on its own (with no addition of external drugs) induce extracellular matrix (ECM) remodeling at human dermal scale, by focusing at genes related to matrisome subset. In this manuscript to be published, electrochemotherapy (ECT) parameters were named SP for "short pulses" and gene electrotransfer (GET) parameters were named LP for "long pulses". W demonstrated that these both types of electric parameters inducing reversible electroporation of the cells whitin the dermal tissue substitute induced 1) a rapid modulation (4h after electrostimulation) of mRNA’s genes composing the matrisome, particularly a down-regulation of pro-collagens and ECM maturation’s enzymes such as transglutaminase TG2 and LOX-like; 2) a transient decrease in pro-collagens production and hydroxyproline tissue content within a week after electrostimulation; 3) a long-lasting ROS-dependent over-activation of MMPs for at least 48h and 4) a down-regulation at both mRNA and protein level of pro-fibrotic TGF-β.

Project description:Electroporation is a versatile method for in vitro or in vivo delivery of different molecules into cells. However, no study so far has analysed the effects of electric pulses used in electrochemotherapy (ECT pulses) or electric pulses used in electrogene therapy (EGT pulses) on malignant cells. We studied the effect of ECT and EGT pulses in human malignant melanoma cells in vitro in order to understand and predict possible effect of electric pulses on gene expression and their possible effect on cell behaviour. We used microarrays with 2698 different oligonucleotides to obtain expression profile of genes involved in apoptosis and development of cancer in a malignant melanoma cell line (SK-MEL28) exposed to ECT pulses and EGT pulses. Cells exposed to ECT pulses showed 68.8% average survival rate and 31.4% average survival rate in cells exposed to EGT pulses. Only seven common genes were found differentially expressed in cells 16 h after exposure to ECT and EGT pulses. We found that ECT and EGT pulses induce HSP70 stress response mechanism, repress histone protein H4, a major protein involved in chromatin assembly, and down-regulate components involved in protein synthesis. Our results show that electroporation does not significantly change expression profile of major tumour suppressor genes or oncogenes of cell cycle. Moreover, electroporation also does not changes the expression of genes involved in stability of DNA, supporting the current evidence that electroporation is a safe method that does not promote tumorigenesis. However, in spite of being considered an isothermal method it does to some extent induce stress that resulted in expression of environmental stress response mechanism, HSP70. The difference in expression of genes involved in development of cancer was obtained by comparison of malignant melanoma cells exposed to EGT or ECT pulses against the same untreated malignant melanoma cells. In our experimental design, microarrays with 2698 different genes were used as a dual colour system in which exposed and non-exposed cellsâ mRNA were separately labelled, mixed and hybridised together on each array. Only microarrays expressing at least 50% of genes were used for further analysis. All oligonucleotides on the same array were spotted in quadruplicates and each microarray analysis was performed in duplicates, therefore obtaining eight measurements of the same oligonucleotide. The acquired data were analysed with Acuity 4.0 to select reliable signals. Only genes, present in both duplicated microarrays were considered for further processing.

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Randomized experimental treatment for colorectal cancer using an endoscopic device in combination with bleomycin or saline.

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