Publications by authors named "Marc Vandamme"

10 Publications

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Mol Pharmacol 2021 May 14. Epub 2021 May 14.

Centre de Recherche des Cordeliers, INSERM UMRS1138, France

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi-target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, concomitant sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. When drugs are administrated sequentially, metformin alters the anti-tumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMPK pathway as well as major transcriptomic changes are associated with the loss of the anti-tumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were co-treated with metformin and sorafenib.
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http://dx.doi.org/10.1124/molpharm.120.000223DOI Listing
May 2021

Iodinated polymer nanoparticles as contrast agent for spectral photon counting computed tomography.

Biomater Sci 2020 Oct 16;8(20):5715-5728. Epub 2020 Sep 16.

University of Lyon 1, LAGEPP, CNRS UMR 5007, 69622 Villeurbanne, France.

Suspensions of iodinated polymer nanoparticles are evaluated as contrast agent for Computed Tomography (CT) and Spectral Photon Counting Computed Tomography (SPCCT). Iodine containing moieties are grafted to poly(vinyl alcohol) by means of a covalent ester bond up to high degree of substitution of 0.77 providing high iodine content of 71 wt%. Polymer nanoparticles of 150 nm diameter stabilized by the block copolymer poly(caprolactone)-b-poly(ethylene glycol) are highly stable in water and human serum. High coverage of nanoparticles by PEG chains in a dense brush conformation (0.30 molecules·nm) provides resistance against fast elimination by mononuclear phagocytes system. Iodine concentration is increased up to 100 mg(i)·mL by a centrifugation/redispersion step, which sets radiopacity of the contrast agent in the right range for imaging cardiovascular system and biodistribution. SPCCT 'Material Decomposition' and 'K-edge reconstruction' methods allow accurate quantification of iodine, as well as specific discrimination of iodine and gadolinium in mixed phantom samples. Intravenous injection of iodinated polymer nanoparticles to rats provides a clear visualization of the cardiovascular system over several hours followed by progressive accumulation in liver and spleen. This material is a 'blood pool' contrast agent with very long residence time in the blood stream.
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http://dx.doi.org/10.1039/d0bm01046dDOI Listing
October 2020

Multicolor spectral photon counting CT monitors and quantifies therapeutic cells and their encapsulating scaffold in a model of brain damage.

Nanotheranostics 2020 22;4(3):129-141. Epub 2020 Apr 22.

CarMeN Laboratory, Institut National de la Santé et de la Recherche Médicale U1060, INRA U1397, Université Lyon 1, INSA Lyon, F-69600 Oullins, France.

: Various types of cell therapies are currently under investigation for the treatment of ischemic stroke patients. To bridge the gap between cell administration and therapeutic outcome, there is a need for non-invasive monitoring of these innovative therapeutic approaches. Spectral photon counting computed tomography (SPCCT) is a new imaging modality that may be suitable for cell tracking. SPCCT is the next generation of clinical CT that allows the selective visualization and quantification of multiple contrast agents. The aims of this study are: (i) to demonstrate the feasibility of using SPCCT to longitudinally monitor and quantify therapeutic cells, i.e. bone marrow-derived M2-polarized macrophages transplanted in rats with brain damage; and (ii) to evaluate the potential of this approach to discriminate M2-polarized macrophages from their encapsulating scaffold. : Twenty one rats received an intralesional transplantation of bone marrow-derived M2-polarized macrophages. In the first set of experiments, cells were labeled with gold nanoparticles and tracked for up to two weeks post-injection in a monocolor study via gold K-edge imaging. In the second set of experiments, the same protocol was repeated for a bicolor study, in which the labeled cells are embedded in iodine nanoparticle-labeled scaffold. The amount of gold in the brain was longitudinally quantified using gold K-edge images reconstructed from SPCCT acquisition. Animals were sacrificed at different time points post-injection, and ICP-OES was used to validate the accuracy of gold quantification from SPCCT imaging. : The feasibility of therapeutic cell tracking was successfully demonstrated in brain-damaged rats with SPCCT imaging. The imaging modality enabled cell monitoring for up to 2 weeks post-injection, in a specific and quantitative manner. Differentiation of labeled cells and their embedding scaffold was also feasible with SPCCT imaging, with a detection limit as low as 5,000 cells in a voxel of 250 × 250 × 250 µm in dimension . : Multicolor SPCCT is an innovative translational imaging tool that allows monitoring and quantification of therapeutic cells and their encapsulating scaffold transplanted in the damaged rat brain.
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http://dx.doi.org/10.7150/ntno.45354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256015PMC
April 2021

Hybrid Nano-GdF contrast media allows pre-clinical in vivo element-specific K-edge imaging and quantification.

Sci Rep 2019 08 20;9(1):12090. Epub 2019 Aug 20.

Laboratoire de Chimie, Université de Lyon, École Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5182, 46 allée d'Italie, 69364, Lyon, France.

Computed tomography (CT) is a widely used imaging modality. Among the recent technical improvements to increase the range of detection for optimized diagnostic, new devices such as dual energy CT allow elemental discrimination but still remain limited to two energies. Spectral photon-counting CT (SPCCT) is an emerging X-ray imaging technology with a completely new multiple energy detection and high spatial resolution (200 μm). This unique technique allows detection and quantification of a given element thanks to an element-specific increase in X-ray absorption for an energy (K-band) depending on its atomic number. The main contrast media used hitherto are iodine-based compounds but the K-edge of iodine (33.2 keV) is out of the range of detection. Therefore, it is crucial to develop contrast media suitable for this advanced technology. Gadolinium, well known and used element for MRI, possess a K-edge (50.2 keV) well suited for the SPCCT modality. The use of nano-objects instead of molecular entities is pushed by the necessity of high local concentration. In this work, nano-GdF is validated on a clinical based prototype, to be used as efficient in vivo contrast media. Beside an extremely high stability, it presents long lasting time in the blood pool allowing perfusion imaging of small animals, without apparent toxicity.
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http://dx.doi.org/10.1038/s41598-019-48641-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702219PMC
August 2019

Impact of Anesthesia Protocols on In Vivo Bioluminescent Bacteria Imaging Results.

PLoS One 2015 24;10(7):e0134048. Epub 2015 Jul 24.

Voxcan, Marcy-l'Etoile, France.

Infectious murine models greatly benefit from optical imaging using bioluminescent bacteria to non-invasively and repeatedly follow in vivo bacterial infection. In this context, one of the most critical parameters is the bioluminescence sensitivity to reliably detect the smallest number of bacteria. Another critical point is the anesthetic approaches that have been demonstrated to impact the bioluminescence flux emission in studies with luciferase-transfected tumor cells. However, this impact has never been assessed on bacteria bioluminescent models. To this end, we investigated the effects of four anesthesia protocols on the bioluminescence flux in a central venous catheter murine model (SKH1-hr(hr) mice) infected by a bioluminescent S. aureus Xen36 strain. Bioluminescence imaging was performed on mice anesthetized by either ketamine/xylazine (with or without oxygen supplementation), or isoflurane carried with air or oxygen. Total flux emission was determined in vivo daily for 3 days and ex vivo at the end of the study together with a CFU counting of the biofilm in the catheter. Bioluminescence flux differences appear between the different anesthetic protocols. Using a ketamine/xylazine anesthesia (with air), bacteria detection was impossible since the bioluminescence signal remains in the background signal. Mice anesthetized with isoflurane and oxygen led to a signal significantly higher to the background all along the kinetics. The use of isoflurane in air presents a bioluminescence signal similar to the use of ketamine/xylazine with oxygen. These data highlight the importance of oxygen to improve bioluminescence flux by bacteria with isoflurane as well as with ketamine/xylazine anesthetics. As a conclusion, we recommend the use of isoflurane anesthetic with oxygen to increase the bioluminescence sensitivity in this kind of study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134048PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514857PMC
May 2016

Synergistic antitumor effect between gefitinib and fractionated irradiation in anaplastic oligodendrogliomas cannot be predicted by the Egfr signaling activity.

PLoS One 2013 18;8(7):e68333. Epub 2013 Jul 18.

Université de Lorraine, CRAN, UMR 7039, Campus Science, Vandoeuvre-les-Nancy, France.

In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment "gefitinib + radiotherapy" and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an "EGFR-addictive" behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for "EGFR-addictive" tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715478PMC
February 2014

Effects of a non thermal plasma treatment alone or in combination with gemcitabine in a MIA PaCa2-luc orthotopic pancreatic carcinoma model.

PLoS One 2012 26;7(12):e52653. Epub 2012 Dec 26.

Centre d'Imagerie du Petit Animal-CIPA TAAM, UPS44 CNRS, Orléans, France.

Pancreatic tumors are the gastrointestinal cancer with the worst prognosis in humans and with a survival rate of 5% at 5 years. Nowadays, no chemotherapy has demonstrated efficacy in terms of survival for this cancer. Previous study focused on the development of a new therapy by non thermal plasma showed significant effects on tumor growth for colorectal carcinoma and glioblastoma. To allow targeted treatment, a fibered plasma (Plasma Gun) was developed and its evaluation was performed on an orthotopic mouse model of human pancreatic carcinoma using a MIA PaCa2-luc bioluminescent cell line. The aim of this study was to characterize this pancreatic carcinoma model and to determine the effects of Plasma Gun alone or in combination with gemcitabine. During a 36 days period, quantitative BLI could be used to follow the tumor progression and we demonstrated that plasma gun induced an inhibition of MIA PaCa2-luc cells proliferation in vitro and in vivo and that this effect could be improved by association with gemcitabine possibly thanks to its radiosensitizing properties.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530450PMC
June 2013

ROS implication in a new antitumor strategy based on non-thermal plasma.

Int J Cancer 2012 May 12;130(9):2185-94. Epub 2011 Aug 12.

GERMITEC SAS, 30 rue Mozart, 92110 CLICHY, France.

Non-thermal plasma (NTP) is generated by ionizing neutral gas molecules/atoms leading to a highly reactive gas at ambient temperature containing excited molecules, reactive species and generating transient electric fields. Given its potential to interact with tissue or cells without a significant temperature increase, NTP appears as a promising approach for the treatment of various diseases including cancer. The aim of our study was to evaluate the interest of NTP both in vitro and in vivo. To this end, we evaluated the antitumor activity of NTP in vitro on two human cancer cell lines (glioblastoma U87MG and colorectal carcinoma HCT-116). Our data showed that NTP generated a large amount of reactive oxygen species (ROS), leading to the formation of DNA damages. This resulted in a multiphase cell cycle arrest and a subsequent apoptosis induction. In addition, in vivo experiments on U87MG bearing mice showed that NTP induced a reduction of bioluminescence and tumor volume as compared to nontreated mice. An induction of apoptosis was also observed together with an accumulation of cells in S phase of the cell cycle suggesting an arrest of tumor proliferation. In conclusion, we demonstrated here that the potential of NTP to generate ROS renders this strategy particularly promising in the context of tumor treatment.
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http://dx.doi.org/10.1002/ijc.26252DOI Listing
May 2012

Radiosensitizing properties of bortezomib depend on therapeutic schedule.

Int J Radiat Oncol Biol Phys 2011 Mar 17;79(3):892-900. Epub 2010 Dec 17.

EA 4421 SiGReTO, UHP Nancy-University, France.

Purpose: To investigate the influence of the bortezomib (BTZ) on malignant glioma radiosensitivity in two xenograft models.

Methods And Materials: For TCG3 and U87 models, we evaluated the antitumor activity of BTZ, radiotherapy, and BTZ plus radiothearapy according to two therapeutic schedules: a "nonfractionated" schedule corresponding to a single dose of treatment per week, and a "fractionated" schedule corresponding to the same weekly dose divided into 5 fractions. Treatments influence on proliferation and apoptosis indexes, cell cycle distribution, and nuclear factor-κB pathway were explored.

Results: The radiosensitizing properties of BTZ observed with the nonfractionated schedule were lost with the fractionated schedule. Bortezomib-mediated radiosensitization was associated with an increased apoptosis response and major changes in cell proliferation, but the nuclear factor-κB pathway was not involved. Most of the cellular effects induced by BTZ when tumors received a single irradiation were cancelled out if radiotherapy was fractionated.

Conclusion: The influence of BTZ on glioma radiosensitivity seems to depend on the treatment fractionation schedule, emphasizing the need to clarify the mechanisms underlying BTZ's radiosensitizing effects before further clinical trials are initiated.
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http://dx.doi.org/10.1016/j.ijrobp.2010.09.051DOI Listing
March 2011