References of "Lechanteur, Chantal"
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See detailRationale for the potential use of mesenchymal stromal cells in liver transplantation
Vandermeulen, M.; DE ROOVER, Arnaud ULg; BRIQUET, Alexandra ULg et al

in World Journal of Gastroenterology (in press)

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See detailInfusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease
Hannon, Muriel ULg; LECHANTEUR, Chantal ULg; Lucas, Sophie et al

in Transfusion (2014), 54(February), 353-363

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See detailImpact of co-transplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning
MOERMANS, Catherine ULg; LECHANTEUR, Chantal ULg; BAUDOUX, Etienne ULg et al

in Transplantation (2014), 98(3), 348-353

Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal ... [more ▼]

Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal models, MSC were shown to cause pulmonary alterations after systemic administration. The impact of MSC infusion on lung function has not been studied in humans. The objective of the study was to investigate the impact of MSC co-infusion on lung function and airway inflammation as well as on the incidence of pulmonary infections and cytomegalovirus (CMV) reactivation after HSCT. Methods: We have prospectively followed 30 patients who underwent unrelated HSCT with MSC co-infusion after non-myeloablative conditioning (NMA). Each patient underwent detailed lung function testing (FEV1, FVC, FEV1/FVC, RV, TLC, DLCO and KCO) and measurement of exhaled nitric oxide before HSCT and 3, 6 and 12 months posttransplant. The incidence of pulmonary infections and CMV reactivation were also monitored. This group was compared with another group of 28 patients who underwent the same type of transplantation but without MSC co-infusion. Results: Lung function tests did not show important modifications over time and did not differ between the MSC and control groups. There was a higher 1-year incidence of infection, particularly of fungal infections, in patients having received a MSC co-infusion. There was no difference between groups regarding the 1-year incidence of CMV reactivation. Conclusions: MSC co-infusion does not induce pulmonary deterioration 1 year after HSCT with NMA conditioning. MSC appear to be safe for the lung but close monitoring of pulmonary infections remains essential. [less ▲]

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See detailLarge-Scale Clinical Expansion of Mesenchymal Stem Cells in the GMP-Compliant, Closed Automated Quantum® Cell Expansion System: Comparison with Expansion in Traditional T-Flasks
LECHANTEUR, Chantal ULg; Baila, Stefano; Janssen, Michel Etienne et al

in Journal of Stem Cell Research & Therapy (2014), 4(8),

Objectives: Significant advances have been achieved regarding the knowledge of the immunoregulatory properties of mesenchymal stem cells (MSC). We are currently involved in several clinical protocols ... [more ▼]

Objectives: Significant advances have been achieved regarding the knowledge of the immunoregulatory properties of mesenchymal stem cells (MSC). We are currently involved in several clinical protocols evaluating these properties in different settings including hematopoietic cells or solid organ transplantation, and severe or refractory autoimmune disorders. Considering the large number of ex-vivo expanded cells required for these clinical protocols (MSC dose varies from 1 to 4x10-6 MSC/kg patient per infusion), we evaluated the Quantum® device, a GMPcompliant, functionally closed, automated hollow fiber bioreactor system and compared it with our traditional clinical culture system in flasks. Methods: Primary and pre-enriched MSC expansions were simultaneously conducted in both culture systems and evaluated in terms of expansion rates and compliance with quality specifications and ISCT-release criteria. Due to practical considerations, most of the experiments conducted in the bioreactor (P1 and P2 expansions) used thawed MSC. These were compared with both fresh and thawed MSC expansions in flasks. Results: The Quantum® device reproducibly produced therapeutic MSC doses that fulfill ISCT-release criteria, are sterile, devoid of mycoplasma and endotoxin, have normal karyotypes and demonstrate immunosuppressive and differentiation capacities in vitro. Cells also grew faster in the bioreactor than in flasks during passage P1 (doubling time 40 compared to 56 hours in flasks) and P2 expansions but not during the primary expansion phase (P0). Seeding 20x10-6 thawed P2-preselected cells on the device allowed us to harvest 110-276x10-6 MSC after a 7 day expansion; seeding 50x10-6 cells resulted in 291-334x10-6 MSC harvested. Conclusion: In conclusion, the Quantum® device is an excellent system to produce a clinical dose of MSC but cost-effectiveness varies as a function of the manufacturing strategy in place. For our particular situation, the use of the Quantum device didn't result in a cost saving solution. [less ▲]

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See detailHuman bone marrow, umbilical cord or liver mesenchymal stromal cells fail to improve liver function in a model of CCl4-induced liver damage in NOD/SCID/IL-2Ry(null) mice
BRIQUET, Alexandra ULg; GREGOIRE, Céline ULg; Comblain, Fanny ULg et al

in Cytotherapy (2014), 16

Background aims. Transplantation is the gold standard procedure for treating acute and chronic end-stage liver diseases. Given the shortage of organs, the development of cellular sources other than human ... [more ▼]

Background aims. Transplantation is the gold standard procedure for treating acute and chronic end-stage liver diseases. Given the shortage of organs, the development of cellular sources other than human liver is urgent. The main objective of this project was to examine the effect of mesenchymal stromal cell (MSC) (bone marrow, umbilical cord and liver MSCs) intravenous injection on liver regeneration in a model of hepatic damage in NOD/SCID/IL non-obese diabetic/severe combined immunodeficient/Interleukin-2Rg(null) (NSG) mice. Methods. Mice received 3 intraperitoneal injections of CCl4 Carbon tetrachloride per week for 4 weeks. Forty-eight hours after the last injection of CCl4, mice received 500,000 MSCs or phosphate-buffered saline by intravenous injection. We examined hepatic damage by means of quantitative image analysis and blood enzyme analysis 24 h, 1 week or 8 weeks after MSC or phosphate-buffered saline injection. We also examined MSC homing by means of real-time polymerase chain reaction of human albumin. Results. We adapted a model of liver injury in immunodeficient mice. In this model, accumulation of collagen in newly formed scar septa was apparent up to 8 weeks after CCl4 treatment. Human albumin DNA was found in all organs tested. However, intravenous MSC injection, even after CXCR4 C-X-C chemokine receptor type 4 transduction and whatever the origin of MSCs, failed to improve liver damage. Conclusions. In this liver injury model, MSCs were propagated in various tissues, particularly filtering organs. For the treatment of hepatic damage, intravenous administration of moderate doses of MSCs does not appear to be effective. Yet, this adapted liver injury model is appropriate for investigating engraftment of human cells. [less ▲]

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See detailThinking out of the box - New approaches to controlling GVHD
Baron, Frédéric ULg; Humblet-Baron, Stéphanie; Ehx, Grégory ULg et al

in Current Hematologic Malignancy Reports (2014), 9

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD ... [more ▼]

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to bebased on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatmentsstill relies on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed on corticosteroids. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis / treatment in the next decades, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or on injection of lowdose interleukin-2. [less ▲]

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See detailINFUSION OF THIRD-PARTY MESENCHYMAL STEM CELLS (MSC) AFTER KIDNEY AND LIVER TRANSPLANTATION: A PHASE I-II, OPEN-LABEL, CLINICAL STUDY (EudraCT 2011-001822-81 & NCT01429038)
DETRY, Olivier ULg; DELBOUILLE, Marie-Hélène ULg; LECHANTEUR, Chantal ULg et al

Poster (2013, May 30)

MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC ... [more ▼]

MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC infusion after cadaveric kidney and liver transplantation in a prospective phase I-II study, taking advantage of our centre expertise and experience in MSC use in graft-versus-host disease (GVHD) after bone marrow transplantation and using an already functioning GMP-compliant laboratory producing clinical-grade MSC. Secondary end-points will help to evaluate the immunosuppressive potential of MSC after organ transplantation, and the opportunity to develop larger randomised, controlled, phase III trials. After successful transplantation, 10 liver and 10 kidney transplant recipients under standard immunosuppression (tacrolimus, MMF, steroids) will receive an intravenous infusion of 1.5-3x106/kg of third-party MSC on post-operative day 3±2. These patients will be prospectively compared to 10 liver and 10 kidney recipients who meet the inclusion criteria but deny MSC infusion. Safety will be assessed by recording side effects, including opportunistic infections and cancers. Immunosuppressive potential will be evaluated by rejection episode rates, by graft/patient survivals, by immunohistology of 3-months kidney and 6-month liver graft biopsies and by in vitro evaluation of the immunity profile of the recipients. In a second step, reduction (kidney) and progressive weaning (liver) of immunosuppression will be attempted in recipients who received MSC. This ongoing study is supported by research grants from the CHU of Liège, University of Liège, and by the Senior Clinical Research Grant from ESOT. The first patients were included and treated in early 2012, and final results expected in late 2013. [less ▲]

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See detailImpact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease
Bruck, France; Belle, Ludovic ULg; LECHANTEUR, Chantal ULg et al

in Cytotherapy (2013), 15(3), 267-279

Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous ... [more ▼]

Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSCs) could exert potent immunosuppressive effects. Methods. The ability of human bone marrow derived MSCs to prevent xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rg(null) (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) was assessed. Results. Injection of 200 106 human PBMCs intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 106 MSCs IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Similarly, injection of 30 106 human PBMCs IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 106 MSCs IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Conclusions. Injection of MSCs did not prevent xenogeneic GVHD in these two humanized mice models. [less ▲]

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See detailInfusion of third party mesenchymal stem cells (MSC) after kidney and liver transplantation: a phase I-II, open-label, clinical study
DETRY, Olivier ULg; DELBOUILLE, Marie-Hélène ULg; LECHANTEUR, Chantal ULg et al

Conference (2012, October 19)

MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC ... [more ▼]

MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC infusion after cadaveric kidney and liver transplantation in a prospective phase I-II study, taking advantage of our centre expertise and experience in MSC use in graft-versus-host disease (GVHD) after bone marrow transplantation and using an already functioning GMP-compliant laboratory producing clinical-grade MSC. Secondary end-points will help to evaluate the immunosuppressive potential of MSC after organ transplantation, and the opportunity to develop larger randomised, controlled, phase III trials. After successful transplantation, 10 liver and 10 kidney transplant recipients under standard immunosuppression (tacrolimus, MMF, steroids) will receive an intravenous infusion of 1.5-3x106/kg of third-party MSC on post-operative day 3±2. These patients will be prospectively compared to 10 liver and 10 kidney recipients who meet the inclusion criteria but deny MSC infusion. Safety will be assessed by recording side effects, including opportunistic infections and cancers. Immunosuppressive potential will be evaluated by rejection episode rates, by graft/patient survivals, by immunohistology of 3-months kidney and 6-month liver graft biopsies and by in vitro evaluation of the immunity profile of the recipients. In a second step, reduction (kidney) and progressive weaning (liver) of immunosuppression will be attempted in recipients who received MSC. This ongoing study is supported by research grants from the CHU of Liège, University of Liège, and by the Senior Clinical Research Grant from ESOT. The first patients were included and treated in early 2012, and final results expected in late 2013. [less ▲]

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See detailBone marrow-derived mesenchymal stromal cells failed to prevent experimental xenogeneic graft-versus-host disease
Bruck, France; de Leval, Laurence; Belle, Ludovic ULg et al

Poster (2012)

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See detailCotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning.
Baron, Frédéric ULg; Lechanteur, Chantal ULg; Willems, Evelyne ULg et al

in Biology of Blood & Marrow Transplantation (2010), 16(6), 838-47

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD ... [more ▼]

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe. [less ▲]

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See detailThe umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood.
Zeddou, Mustapha ULg; Briquet, Alexandra ULg; Relic, Biserka ULg et al

in Cell Biology International (2010), 34(7), 693-701

Many studies have drawn attention to the emerging role of MSC (mesenchymal stem cells) as a promising population supporting new clinical concepts in cellular therapy. However, the sources from which these ... [more ▼]

Many studies have drawn attention to the emerging role of MSC (mesenchymal stem cells) as a promising population supporting new clinical concepts in cellular therapy. However, the sources from which these cells can be isolated are still under discussion. Whereas BM (bone marrow) is presented as the main source of MSC, despite the invasive procedure related to this source, the possibility of isolating sufficient numbers of these cells from UCB (umbilical cord blood) remains controversial. Here, we present the results of experiments aimed at isolating MSC from UCB, BM and UCM (umbilical cord matrix) using different methods of isolation and various culture media that summarize the main procedures and criteria reported in the literature. Whereas isolation of MSC were successful from BM (10:10) and (UCM) (8:8), only one cord blood sample (1:15) gave rise to MSC using various culture media [DMEM (Dulbecco's modified Eagle's medium) +5% platelet lysate, DMEM+10% FBS (fetal bovine serum), DMEM+10% human UCB serum, MSCGM] and different isolation methods [plastic adherence of total MNC (mononuclear cells), CD3+/CD19+/CD14+/CD38+-depleted MNC and CD133+- or LNGFR+-enriched MNC]. MSC from UCM and BM were able to differentiate into adipocytes, osteocytes and hepatocytes. The expansion potential was highest for MSC from UCM. The two cell populations had CD90+/CD73+/CD105+ phenotype with the additional expression of SSEA4 and LNGFR for BM MSC. These results clearly exclude UCB from the list of MSC sources for clinical use and propose instead UCM as a rich, non-invasive and abundant source of MSC. [less ▲]

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See detailCo-transplantation of mesenchymal stem cells might mitigate acute GvHD without abrogating graftversus- tumour alloreactivity after allogeneic transplantation with non-myeloablative conditioning
Baron, Frédéric ULg; WILLEMS, Evelyne ULg; LECHANTEUR, Chantal ULg et al

Conference (2009)

Background: Results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested that ... [more ▼]

Background: Results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested that infusion of mesenchymal stem cells (MSC) the day of HCT might promote engraftment and prevent acute GVHD after myeloablative allogeneic HCT. However, some studies suggested that MSC co-infusion might abrogate graft-versus-host alloreactivity and graft-versus-tumor effects. This prompted us to investigate whether MSC infusion a few hours before HCT could allow nonmyeloablative HCT from HLA-mismatched donors to be performed safely (i.e. with a 100-day incidence of nonrelapse mortality < 35%). Methods: 20 patients with hematological malignancies were given MSC (1-2 x 10E6 cells/kg) from third party donors a few hours before PBSC from HLA-mismatched unrelated donors, after conditioning with 2 Gy TBI and fl udarabine 90 mg/m. Postgrafting immunosuppression included tacrolimus (day -3 to +180; tapered by day +365) and mycophenolate mofetil (tid days 0 to +42). HLA-compatibility was assessed at the HLA-A, -B, -C, -DRBI and DQBI loci: 13 pairs were mismatched for at least one HLA class I antigen (including 4 pairs who were also mismatched for 1 HLA-class II antigens (n=3) or 1 HLA-class I allele (n=1)), 1 pair was mismatched for 2 HLA class II alleles, while 6 pairs were mismatched for a single HLA class I (n=3) or HLA class II (n=3) alleles. Results: Median follow-up for surviving patients was 288 (range, 76-571) days. One patient with secondary AML had primary graft rejection, while the remaining 19 patients had sustained engraftment. Median donor T-cell chimerism levels on days 28, 100, 180 and 365 after HCT were 90%, 98%, 96%, and 98%, respectively. Grade II, III and IV acute GVHD were seen in 5, 2 and 1 patients, respectively, while 7 experienced NIH moderate/severe chronic GVHD. Three of 7 patients with measurable disease at transplantation achieved complete remission on days 41, 104 and 353 after HCT. Two patients died of nonrelapse causes on days 74 and 114 after HCT, while 3 died of disease progression. Projected 1-yr overall and progressionfree survivals were 77% and 61%, respectively. Conclusions: HLA-mismatched nonmyeloablative HCT with MSC co-infusion appeared to be safe, with MSC co-infusion possibly mitigating graft-versus-host alloreactivity without abrogating graft-versus-tumor effects. Survival is encouraging. [less ▲]

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See detailSufasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas
Robe, Pierre ULg; Nguyen-Khac, Minh-Tuan ULg; Lambert, Frédéric ULg et al

in International Journal of Oncology (2007), 30(1), 283-290

The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased ... [more ▼]

The efficacy of HSV-TK/ganciclovir-based gene therapy on malignant gliomas largely relies on the amplitude of the bystander effect. In these experiments, the anti-inflammatory drug Sulfasalazine increased the HSV-TK/ganciclovir bystander effect in C6, 9L and LN18 cells but not in U87 glioma cells. Using bi-compartmental culture devices and conditioned medium transfer experiments, we showed that in C6, 9L and LN18 cells but not in U87 cells, Sulfasalazine also unveiled a new, contact-independent mechanism of HSV-TK/ganciclovir bystander effect. Upon treatment with ganciclovir, human LN18-TK but not U87-TK cells synthetized and released TNF-alpha in the culture medium. Sulfasalazine sensitized glioma cells to the toxic effect of TNF-alpha. and enhanced its secretion in LN18-TK cells in response to GCV treatment. The caspase-8 inhibitor Z-IETD-FMK and a blocking antibody to TNF-alpha both inhibited the contact-independent bystander effect in LN18 cells. Taken together, these results suggest that TNF-alpha mediates the contact-independent bystander effect in LN18 cells. The treatment with GCV and/or Sulfasalazine of tumor xenografts consisting of a mix of 98% C6 and 2% C6-TK cells shows that Sulfasalazine is also a potent adjunct to the in vivo treatment of gliomas. [less ▲]

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See detailLow daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis
Lechanteur, Chantal ULg; Jacobs, Nathalie ULg; Greimers, Roland ULg et al

in Oncogene (2005), 24(10), 1788-1793

Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells ... [more ▼]

Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells distant from blood vessels (hypoxic cells) are exposed to low drug concentrations. In this report, we show that low daunomycin concentrations protect HCT116 colorectal cancer cells from hypoxia-induced apoptosis. While hypoxia induced p53 accumulation without expression of its responsive genes (bax and p21), daunomycin treatment restored p53 transactivation activity and cell cycle progression. We also demonstrated a role for Akt activation in daunomycin-induced protection through phosphorylation and inactivation of the Bcl-2 family proapoptotic factor Bad. Our data therefore suggest that chemotherapy could possibly, because of low concentrations in poorly vascularized tumors, protect cancer cells from hypoxia-induced cytotoxicity. [less ▲]

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See detailCombined Suicide and Cytokine Gene Therapy for Peritoneal Carcinomatosis
Lechanteur, Chantal ULg; Delvenne, Philippe ULg; Princen, Frédéric et al

in Gut (2000), 47(3), 343-8

BACKGROUND: Gene therapy is a novel approach for the treatment of cancers, and tumours disseminated in the peritoneal cavity are suitable for in situ delivery of a therapeutic gene. AIMS: The efficacy of ... [more ▼]

BACKGROUND: Gene therapy is a novel approach for the treatment of cancers, and tumours disseminated in the peritoneal cavity are suitable for in situ delivery of a therapeutic gene. AIMS: The efficacy of a therapy combining a suicide gene (herpes simplex virus type I thymidine kinase (HSV-TK)) and cytokine genes was investigated in a model of peritoneal carcinomatosis induced by colon carcinoma cells in syngeneic rats. MATERIAL AND METHODS: Pre-established macroscopic tumours in BDIX rats were treated by intraperitoneal injections of retrovirus producing cells (FLYA13 TK, FLYA13 granulocyte macrophage-colony stimulating factor (GM-CSF), FLYA13 interleukin 12 (IL-12)) and ganciclovir (GCV). RESULTS: TK/GCV treated animals showed a slight increase in survival time (72 days) compared with the control group (63 days) while the association of cytokine and TK/GCV gene therapy resulted in significantly improved survival, with a large proportion of animals remaining tumour free on day 480 (60% and 40% for TK/GCV/GM-CSF and TK/GCV/IL-12 treated animals, respectively). Histological analysis of treated animals showed that the remaining tumour nodes were infiltrated by mononuclear cells but no major differences were observed between the various treatments. Immunohistochemical analysis revealed that lymphoid CD4(+) and CD8(+) T cells as well as macrophages accumulated outside untreated tumour nodes while CD8(+) and CD25(+) activated T cells and macrophages heavily infiltrated the tumours after the different treatments. CONCLUSIONS: Our data indicate that combined suicide and cytokine gene therapy is a powerful approach for the treatment of macroscopic peritoneal carcinomatosis. [less ▲]

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See detailAntitumoral Vaccination with Granulocyte-Macrophage Colony-Stimulating Factor or Interleukin-12-Expressing Dhd/K12 Colon Adenocarcinoma Cells
Lechanteur, Chantal ULg; Moutschen, Michel ULg; Princen, Frederic et al

in Cancer Gene Therapy (2000), 7(5), 676-82

Immunomodulating gene therapy for the treatment of malignant diseases is under extensive investigation. In this study, we induced an antitumoral immune response with murine interleukin-12 (mIL-12) and ... [more ▼]

Immunomodulating gene therapy for the treatment of malignant diseases is under extensive investigation. In this study, we induced an antitumoral immune response with murine interleukin-12 (mIL-12) and murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cells in a model of peritoneal carcinomatosis. Intraperitoneal injection of DHD/K12 tumoral cells engineered to produce IL-12 or GM-CSF did not generate any tumors, whereas untransduced DHD/K12 cells gave rise to peritoneal carcinomatosis. IL-12-expressing DHD/K12 cells also protected against tumors derived from coinjected parental cells. To test whether cytokine-producing cells could elicit a memory antitumoral immune response, animals received a challenge with parental DHD/K12 cells 35 days after the injection of proliferating or irradiated DHD/K12 engineered cells. Under our experimental conditions, irradiated tumor cells did not generate any antitumoral immunity. In contrast, tumor development was delayed and survival increased in the animals vaccinated with cytokine-secreting proliferating cells. A specific cytotoxic T-lymphocyte response against DHD/K12 parental cells was observed after vaccination with GM-CSF-expressing cells. Our results demonstrated that intraperitoneal vaccination with IL-12- or GM-CSF-expressing adenocarcinoma cells induced a systemic immune antitumoral response that may be useful as an adjuvant therapy after surgical resection of colorectal cancer. [less ▲]

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See detailCytosine Deaminase Suicide Gene Therapy for Peritoneal Carcinomatosis
Bentires-Alj, M.; Hellin, A. C.; Lechanteur, Chantal ULg et al

in Cancer Gene Therapy (2000), 7(1), 20-6

Gene therapy is a novel therapeutic approach that might soon improve the prognosis of some cancers. We investigated the feasibility of cytosine deaminase (CD) suicide gene therapy in a model of peritoneal ... [more ▼]

Gene therapy is a novel therapeutic approach that might soon improve the prognosis of some cancers. We investigated the feasibility of cytosine deaminase (CD) suicide gene therapy in a model of peritoneal carcinomatosis. DHD/K12 colorectal adenocarcinoma cells transfected in vitro with the CD gene were highly sensitive to 5-fluorocytosine (5-FC), and a bystander effect could also be observed. Treating CD+ cells with 5-FC resulted in apoptosis as detected by terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling. In vitro, several human cell lines derived from ovarian or colorectal carcinomas, as well as the rat glioblastoma 9 L cell line, responded to CD/5-FC and showed a very strong bystander effect. 5-FC treatment of peritoneal carcinomatosis generated in syngeneic BDIX rats by CD-expressing DHD/K12 cells led to a complete and prolonged response and to prolonged survival. Our study thus demonstrated the efficacy of CD suicide gene therapy for the treatment of peritoneal carcinomatosis. [less ▲]

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