Biomedical subjects

Olivier Soubrane

Publications and source records attributed to Olivier Soubrane.

At least 19 recordsLinked to original sources

PubMed2007

A novel, sensitive, and specific RT-PCR technique for quantitation of hepatitis C virus replication.

The detection of negative-strand hepatitis C virus (HCV) RNA is a hallmark of replication. A highly sensitive and specific method is required to quantify the very low level of replication inherent to in vitro infection systems. Based on reverse transcription with a tagged primer in the 5' non-coding region of the HCV genome, followed by a nested PCR with a second round of real-time PCR, a novel method is described with improved sensitivity for negative-strand HCV RNA quantification. The lower detection level was 25 copies per reaction of negative-strand HCV RNA, even in the presence of 1 x 10(5) copies of positive-strand HCV RNA. This protocol was applied to the detection of negative HCV strand RNA in the liver of HCV-infected patients as well as in primary human hepatocytes infected in vitro. In both models, and particularly in each of three, independent in vitro infection experiments, this assay permitted the quantitation of HCV replication.

Cells, Cultured↗

PubMed2006

Impaired erythropoietin production in liver transplant recipients: the role of calcineurin inhibitors.

Anemia is common following liver transplantation. Because cyclosporine inhibits erythropoietin (Epo) production in experimental models, we investigated whether Epo production was impaired in liver transplant recipients receiving a cyclosporine- or tacrolimus-based immunosuppressive regimen. First, serum Epo levels were measured before and 1 year after transplantation in 35 liver transplant recipients. Second, serum Epo levels were compared in a large series of liver transplant recipients with stable graft and renal functions: 27 receiving a cyclosporine-based and 31 receiving a tacrolimus-based immunosuppressive regimen. A reference group was made up of 22 blood donors and 21 nontransplanted subjects with iron-deficiency anemia. Serum Epo levels were significantly lower after than before liver transplantation, especially in cyclosporine-treated patients. Serum Epo concentrations correlated with hematocrit values in both transplant recipients and control subjects. Using multiple linear regression models, the polynomial relationship between hematocrit and serum Epo values was similar to the control group in patients under tacrolimus, whereas Epo production was significantly reduced in patients under cyclosporine-based immunosuppression. Hematocrit values and the type of calcineurin inhibitor were the only parameters independently related to Epo levels. In conclusion, cyclosporine, but not tacrolimus, inhibits Epo production at the doses used in clinical practice.

Adult↗

PubMed2006

Liver repopulation trial using bone marrow cells in a retrorsine-induced chronic hepatocellular injury model.

OBJECTIVES: The aim of this study was to determine the potential of bone marrow derived cells to participate in liver repopulation. In this model, the injected cells had a "selective growth advantage" compared to the native hepatocytes whose proliferation was blocked by retrorsine. METHODS: Total bone marrow cells were isolated from male Fisher 344 rats not deficient in dipeptidyl peptidase activity (F344, DPP IV+). The animals were given an injection of retrorsine and were divided in 2 groups: 1/group R (N=13): female F344 rats received 4.106 male cells at day 0 (labeled by chromosome Y). 2/group RH (N=19): Male F344 DPP IV- rats received 4.106 male DPP IV+ cells after hepatectomy at day 0 (labelled by DPP IV activity). RESULTS: Group R: no male cell was detected by PCR at day 14, 28, 56 and 84. Group RH: isolated DPP IV+ transplanted cells were observed at days 14 and 28 in the periportal areas. Later, these cells were no longer visible. Liver regeneration occurred by proliferation of small clusters of hepatocytes. CONCLUSIONS: In this experimental model the capacity of transplanted bone marrow cells to repopulate the liver was tested against the same capacity of native liver stem cells. Liver regeneration occurred via native liver cells seen as small hepatocytes. In this model the small hepatocytes may be considered as hepatic stem cells.

Animals↗

PubMed2006

[Recurrent hepatitis C after liver transplantation: Erythropoietin allows maintenance of antiviral treatment].

INTRODUCTION: Hepatitis C recurs on grafts after liver transplantation and cirrhosis develops more rapidly than in patients without transplants. It is thus essential to develop effective antiviral treatments for these patients. Prolonged virologic response rate after treatment by pegylated interferon and ribavirin of recurrent HVC is limited, because so many patients stop or reduce the treatment because, in particular, of profound anemia. Administration of erythropoietin can enable these patients to continue treatment and thus improve viral eradication. CASES: We report three cases where antiviral treatment continued although the clinical data would, in the absence of erythropoietin, have led us to interrupt it and where prolonged virologic response was obtained. DISCUSSION: These data suggest that the onset of anemia largely explains the failure of previous trials, although response to treatment is at least as good as in non-transplanted patients, despite immunosuppressive treatment.

Anemia↗

PubMed2006

Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center.

BACKGROUND DATA AND OBJECTIVE: Left lateral sectionectomy for liver transplantation in children performed through laparoscopy is an innovative procedure that was developed by considering our acquired experience in both laparoscopic liver resection and graft harvesting in living donors. The main goal was to minimize donor morbidity while preserving the abdominal wall. Herein, we report the technical feasibility and reproducibility, and compared it with open liver resection (OLR). METHODS: Sixteen successive donors underwent a laparoscopic liver resection (LLR) from 2001 to 2005. They were compared with 14 other donors who underwent a standard open liver resection (OLR) during a first period (1998-2004). First, this report describes the technical features of laparoscopic resection. Second, perioperative morbidity and graft characteristics were compared according to the use or not of the laparoscopic approach. RESULTS: Laparoscopic harvesting was successfully performed in 15 of 16 cases in an intention-to-treat basis. One conversion was required to ensure the quality of the laparoscopic repair of a left portal vein injury occurring during the pedicle dissection. No specific complication related to laparoscopy was observed. As compared with OLR, the operation was longer (320 +/- 67 vs. 244 +/- 55 minutes, P < 0.005). The blood loss was significantly lower in the LLR group (18.7 +/- 44.2 vs. 199.2 +/- 185.4 mL, P < 0.005). The morbidity rate was similar in both groups (18.7% in LLR vs. 35.7% in OLR). One donor in the LLR group experienced a bile leak treated by redo laparoscopy. Grafts were anatomically similar irrespective of the use of laparoscopy. The duration of hospital stay and use of self-infused morphine pump was not different between the 2 groups. CONCLUSION: Left lateral section harvesting by laparoscopy is a safe and reproducible procedure, allowing to obtain similar grafts as compared with laparotomy and can therefore be recommended to transplant centers that have previous experience in laparoscopic liver resection.

Adult↗

PubMed2005

Controlling tumor growth by modulating endogenous production of reactive oxygen species.

Paradoxically, reactive oxygen species (ROS) can promote normal cellular proliferation and carcinogenesis, and can also induce apoptosis of tumor cells. In this report, we study the contribution of ROS to various cellular signals depending on the nature and the level of ROS produced. In nontransformed NIH 3T3 cells, ROS are at low levels and originate from NADPH oxidase. Hydrogen peroxide (H(2)O(2)), controlled by the glutathione system, is pivotal for the modulation of normal cell proliferation. In CT26 (colon) and Hepa 1-6 (liver) tumor cells, high levels of ROS, close to the threshold of cytotoxicity, are produced by mitochondria and H(2)O(2) is controlled by catalase. N-acetylcysteine, which decreases H(2)O(2) levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H(2)O(2) concentration drops from the toxicity threshold. In contrast, antioxidant molecules, such as mimics of superoxide dismutase (SOD), increase H(2)O(2) levels through superoxide anion dismutation, as well as in vitro proliferation of normal cells, but kill tumor cells. CT26 tumors were implanted in mice and treated by oxaliplatin in association with one of the three SOD mimics manganese(III)tetrakis(4-benzoic acid) porphyrin, copper(II)(3,5-diisopropylsalicylate)2, or manganese dipyridoxyl diphosphate. After 1 month, the volumes of tumors were respectively 35%, 31%, and 63% smaller than with oxaliplatin alone (P < 0.001). Similar data were gained with Hepa 1-6 tumors. In conclusion, antioxidant molecules may have opposite effects on tumor growth. SOD mimics can act in synergy with cytotoxic drugs to treat colon and liver cancers.

Animals↗

PubMed2005

HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice.

Human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein HIP/PAP is a secreted C-type lectin belonging to group VII, according to Drickamer's classification. HIP/PAP is overexpressed in liver carcinoma; however, its functional role remains unclear. In this study, we demonstrate that HIP/PAP is a paracrine hepatic growth factor promoting both proliferation and viability of liver cells in vivo. First, a low number of implanted hepatocytes deriving from HIP/PAP-transgenic mice (<1:1,000) was sufficient to stimulate overall recipient severe combined immunodeficiency liver regeneration after partial hepatectomy. After a single injection of HIP/PAP protein, the percentages of bromodeoxyuridine-positive nuclei and mitosis were statistically higher than after saline injection, indicating that HIP/PAP acts as a paracrine mitogenic growth factor for the liver. Comparison of the early events posthepatectomy in control and transgenic mice indicated that HIP/PAP accelerates the accumulation/degradation of nuclear phospho-signal transducer activator transcription factor 3 and tumor necrosis factor alpha level, thus reflecting that HIP/PAP accelerates liver regeneration. Second, we showed that 80% of the HIP/PAP-transgenic mice versus 25% of the control mice were protected against lethal acetaminophen-induced fulminate hepatitis. A single injection of recombinant HIP/PAP induced a similar cytoprotective effect, demonstrating the antiapoptotic effect of HIP/PAP. Comparison of Cu/Zn superoxide dismutase activity and glutathione reductase-like effects in control and transgenic liver mice indicated that HIP/PAP exerts an antioxidant activity and prevents reactive oxygen species-induced mitochondrial damage by acetaminophen overdose. In conclusion, the present data offer new insights into the biological functions of C-type lectins. In addition, HIP/PAP is a promising candidate for the prevention and treatment of liver failure.

Acetaminophen↗

PubMed2005

Long-term outcome of pediatric liver transplantation for biliary atresia: a 10-year follow-up in a single center.

The aim of this study was to review our experience in orthotopic liver transplantation (OLT) for biliary atresia (BA) in children and analyze the survival and prognostic factors, and long-term outcome. We reviewed 332 OLTs performed in 280 children between the years 1986 and 2000. Univariate and multivariate analysis were performed on patient and graft survivals according to recipients' and donors' characteristics as well as intraoperative data. The long-term outcome among the 80 children living at 10 years after OLT was studied according to growth, immunosuppressive therapy, and liver and renal functions. Liver graft status was eventually documented by liver biopsy. Status of rehabilitation was assessed by reviewing school performance and employment. Overall patient survival rates at 1, 5, and 10 years were 85, 82, and 82%, respectively, and the corresponding overall graft survival rates were 77, 73, and 71%. In the multivariate analysis, we identified 4 independent prognostic factors: polysplenia syndrome (P = .03), United Network for Organ Sharing (UNOS) status (P = .05), donor's age (P = .01), and perioperative surgical complications (P = .03). At 10 years after transplant, 80 children were alive and had normal growth rates. Liver histology was abnormal in 73% of these long-term survivors, mainly due to chronic rejection and centrilobular fibrosis. A total of 63 of the 80 children attended normal school and in 55 children (69%) school performance was not delayed. In conclusion, we discovered that a good long-term survival could be achieved after liver transplantation for BA, with a 82% survival rate at 10 years with normal scholastic studies in the majority of recipients.

Adolescent↗

PubMed2004

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis.

Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O(2)*- than those of lean littermates (P <.01). Ex vivo, all three SOD mimics decreased O(2)*- generation (P <.001) and totally inhibited lipid peroxidation (P <.001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P <.02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in humans.

Animals↗

PubMed2004

Major liver resection without clamping: a prospective reappraisal in the era of modern surgical tools.

BACKGROUND: Hemorrhage and transfusions remain the main causes of mortality and morbidity from liver resection. In cases of extended resection, especially performed on diseased liver, ischemia-reperfusion injury related to pedicle clamping may be a significant risk factor of postoperative liver dysfunction. The ideal alternative would be to perform major hepatectomy without clamping and without significant bleeding. STUDY DESIGN: This prospective study aimed to reconsider the risk of major hepatectomy performed without pedicle clamping and under low venous pressure in the light of modern surgical tools. Inclusion criteria were adults requiring a resection of more than three segments on healthy or pathologic livers but not on preoperative documented cirrhosis. RESULTS: Fifty patients, with a mean age of 53 +/- 15 years were included. Twenty-two patients had underlying liver disease. The main indications were colorectal metastases, primary liver tumors, and living donation. Twenty-six right hepatectomies, 17 extended right hepatectomies, and 7 extended left hepatectomies were performed. Unclamping method was successful in 96% of patients on an intention-to-treat basis. Seventy-four percent of patients were not transfused and no patients died. Surgical complication rate was 16% but no complication led to reoperation. Medical complication rate was 20%, including three transient liver dysfunctions. CONCLUSIONS: Major hepatectomy without clamping can be performed safely. The low rate of postoperative liver dysfunction, especially in cases of underlying liver disease, suggests good preservation of the small and diseased remnant liver.

Adult↗

PubMed2004

Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases.

In humans, no efficient treatment exists not only against multifocal liver metastases (LM) but also against recurrent microscopic liver metastases within the liver remnant following curative liver resection. Furthermore, in nonmultifocal LM, partial liver resection could be performed, but in more than 50% of the patients, tumor recurrence within liver remnant is observed, partly due to the growth of dormant cancer cells in the setting of postoperative host immune dysfunction. We investigated the therapeutic potential of interleukin-12 (IL-12) immuno-gene therapies in these experimental models under total vascular exclusion (TVE) of the liver. In rats with multiple LM of DHDK12 colon cancer cells, we observed a significant reduction in tumor volume after retroviral-mediated gene transfer of either herpes simplex virus thymidine kinase (HSV1-TK) and ganciclovir (GCV) administration, or IL-12. Combined treatment with HSV1-TK/GCV and IL-12 resulted in improved tumor volume reduction and even survival. In rats with recurrent microscopic DHDK12 LM established after partial liver resection, we observed significantly decreased recurrent tumor volumes and increased survival after retroviral-mediated IL-12 gene transfer. In both settings, immunohistological analysis revealed that IL-12 immuno-gene therapy was accompanied by an infiltration of CD8+ T lymphocytes within the tumors. Altogether, our results suggest that IL-12 adjuvant gene therapy could improve the management of patients with either resectable or unresectable LM.

Animals↗

PubMed2004

Use of lidocaine metabolism to test liver function during the long-term follow-up of liver transplant recipients.

BACKGROUND/AIMS: The aim of this study was to assess the usefulness of the monoethylglycinexylidide (MEGX) test to monitoring the long-term function of liver allografts. METHODS: MEGX production was measured prospectively in 60 consecutive liver transplant recipients undergoing their annual review. RESULTS: Median MEGX values in liver recipients (54 ng/mL; range 10-146) were lower than those found in healthy controls (78 ng/mL; range 44-118). MEGX values correlated negatively with alanine aminotransferase (ALT) activity (p = 0.004) and with the overall histological score (p = 0.01), and positively with sulfobromophthalein (BSP) and indocyanine green (ICG) clearances (p = 0.0002 and p = 0.002, respectively). A stepwise decline was observed with worsening liver fibrosis, from 71 +/- 5 microg/L in patients with no fibrosis to 27 +/- 9 microg/L in patients with bridging fibrosis (p = 0.002). BSP and ICG clearances correlated more closely than the MEGX test with the overall histological score (p = 0.001 and p = 0.001, respectively) and portal fibrosis (p = 0.002 and p = 0.001). CONCLUSIONS: The measurement of MEGX formation is a simple and non-invasive method to monitor liver graft function. It may constitute a valuable tool for assessing the degree of fibrosis.

Adolescent↗

PubMed2004

The effect of erythropoietin on allogeneic blood requirement in patients undergoing elective liver resection: a model simulation.

UNLABELLED: We investigated whether recombinant human erythropoietin (rHuEPO) administration would reduce red blood cell (RBC) transfusion requirements in patients undergoing elective liver resection. We retrospectively investigated 200 patients undergoing elective liver resection. Factors likely to predict perioperative RBC transfusion were studied using a logistic regression analysis. A mathematical model was used to simulate RBC transfusion requirements if (a). transfusion thresholds had been predefined at a hemoglobin concentration of 7-8 g/dL, (b). preoperative hemoglobin concentrations had been increased to 15 g/dL by rHuEPO administration in patients with preoperative hemoglobin concentration in the range 10-13 g/dL, and (c). both interventions had been used. A cost/benefit evaluation of rHuEPO administration formed part of this simulation. RBC transfusion was correlated with major and median liver resection, total liver vascular exclusion, and a combined nonhepatic abdominal surgery but was not correlated with a preoperative hemoglobin concentration in the range 10-13 g/dL. Adherence to a small transfusion threshold or rHuEPO administration alone would have resulted in a slight reduction in transfusion requirements and transfusion rates for the whole population. However, the two interventions in combination would have significantly reduced both variables. One-hundred-eighteen patients undergoing median and major liver resection received 92% of RBC transfused. Sixty-six of these 118 patients had preoperative hemoglobin concentrations in the range 10-13 g/dL and could have received rHuEPO before surgery. rHuEPO alone would have avoided the transfusion of 63 RBC packs of 203 in this subgroup and 12 transfused patients of 31 (P = 0.02). rHuEPO administration to these 66 patients would have cost 186000 Euro. The 63 RBC saved would have cost 10,710 Euro. IMPLICATIONS: A mathematical model simulation suggests that the routine preoperative administration of erythropoietin to patients scheduled for major and median liver resection presenting with a preoperative hemoglobin concentration in the range 10-13 g/dL could reduce blood transfusion requirements. However, the cost/benefit ratio warrants consideration.

Aged↗

PubMed2003

Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France.

BACKGROUND: Although the possibility of reversing hepatopulmonary syndrome (HPS) after liver transplantation is now well established, the proportion of patients in whom reversibility is observed and the time to resolution of HPS remain uncertain. METHODS: We analyzed the outcome of all adult patients with HPS who underwent orthotopic liver transplantation in all the liver transplant centers in Paris, during a 10-year period. RESULTS: Twenty-three adult patients (median age, 47 years; range, 14-64) underwent transplantation in four institutions. Median PaO(2) was 52 (range, 32-67) mm Hg and median alveolar-arterial oxygen gradient was 66 mm Hg. When patients were breathing 100% O(2), median PaO(2) was 310 (range, 74-663) mm Hg. Median isotopic shunt ratio was 33% (range, 0-80%). The overall mortality during the study period was 30.5% (7/23). Perioperative mortality was 8.5%, whereas late mortality was 22%. None of the preoperative characteristics of HPS (isotopic shunt ratio, PaO(2) on room air or on 100% oxygen) was associated with overall postoperative mortality. Of the 21 patients surviving the perioperative period (median follow-up, 17 months; range, 0.5-72), a decrease in alveolar-arterial oxygen gradient of at least 5 mm Hg and at least 10 mm Hg was observed in 21 of 21 and in 18 of 21 patients, respectively, with great variations in the time of improvement. The threshold of 70 mm Hg was reached in 15 patients. The lower the preoperative PaO(2), the longer the time to reach this point. CONCLUSION: Our data strongly support the role of orthotopic liver transplantation in adult patients with HPS, regardless of its severity.

Adolescent↗

PubMed2003

Mangafodipir prevents liver injury induced by acetaminophen in the mouse.

BACKGROUND/AIMS: Acute liver failure (ALF), characterized by massive hepatocyte necrosis, is often caused by drug poisoning, particularly with acetaminophen (APAP). Hepatocyte necrosis is consecutive to glutathione depletion by NAPQI, a metabolite of APAP, and to mitochondrial damages caused by reactive oxygen species (ROS) overproduction. Considering the structure of Mangafodipir, a contrast agent currently used in magnetic resonance imaging of the liver, we hypothesized that this molecule could exert an antioxidant activity and be possibly used as a treatment of APAP-induced ALF. METHODS/RESULTS: Mangafodipir is endowed with superoxide dismutase, catalase, and glutathione reductase activities. It can inhibit ROS production by hepatocytes in culture, and protect those cells from oxidative stresses induced by exposure to xanthine oxidase, H(2)O(2), or UV light. Moreover, preventive or curative administration of Mangafodipir to mice with APAP-induced ALF significantly increases survival rates, and abrogates aspartate aminotransferase elevation and histological damage. CONCLUSIONS: Those data point out the potential interest of Mangafodipir in the treatment of toxic ALF in humans.

Acetaminophen↗

PubMed2003

Correlation between daily cyclosporine dose and allograft injury in liver recipients with and without recurrent hepatitis C.

BACKGROUND: After liver transplantation, the daily cyclosporine dose is adjusted to maintain the blood level in a chosen range. The aim of this study was to assess the influence of liver graft injury on cyclosporine dose. METHODS: The parameters of liver function were investigated in 145 patients. Ninety-two patients took part in a longitudinal study. RESULTS: The cyclosporine dose correlated with the MEGX test (r=0.38, P=0.01) and with the ICG (r=0.38, P=0.0001) and BSP (r=0.37, P=0.0002) clearances; it had an inverse correlation with transaminases (AST: r=0.38, P=0.0001) and histological lesions (r=-0.29, P=0.005). The cyclosporine dose was lower in patients with recurrent hepatitis C (179+/-9 mg/day) than in those without (241+/-10 mg/day), and was lower in patients with chronic hepatitis (154+/-9 mg/day) than in those without (207+/-16 mg/day). In the longitudinal study, the percent variation of AST correlated inversely with that of cyclosporine dose (r=-0.62, P=0.0002). CONCLUSION: Progressive graft injury leads to a reduction in the cyclosporine dose, particularly in patients with recurrent hepatitis C.

Journal Article↗

PubMed2003

Total vascular exclusion of the liver enhances the efficacy of retroviral-mediated associated thymidine kinase and interleukin-2 genes transfer against multiple hepatic tumors in rats.

BACKGROUND: Recent advances in gene transfer technology render gene therapy an attractive treatment of disseminated liver metastases for which other treatments remain disappointing. In this setting, total vascular exclusion of the liver could improve gene transfer to cancer cells and prevent extrahepatic vector spreading during portal infusion of therapeutic genes. We evaluate the efficiency of combined herpes simplex virus type-1 thymidine kinase (HSV1-TK) and interleukin-2 retrovirus-mediated gene transfer through the portal vein, under total vascular exclusion of the liver, in a model of macroscopic multiple liver metastases in rats. METHODS: Multifocal liver metastases were established in BDIX rats with intraportal injection of DHDK12 colon cancer cells. On randomization, rats received either vector-producing cells or saline solution under total vascular exclusion of the liver. Vector-producing cells released retroviral vectors encoding Lac-Z in marking studies or HSV1-TK or interleukin-2 in therapeutic studies. Rats were either killed for pathologic studies, or followed for survival. RESULTS: Total vascular exclusion of the liver markedly improved gene transfer efficacy in marking studies. In therapeutic studies we observed a significant reduction in tumor volume of treated rats compared with untreated controls (2170 +/- 310 mm(3)). Although singular HSV1-TK or interleukin-2 gene transfer showed significant efficacy, the greatest tumor volume regression was observed in rats treated with combined HSV1-TK + interleukin-2 gene therapy (145 +/- 60 mm(3); P =.0001 vs control). This translated into an increased median survival rate compared with either control rats (P =.006) or rats treated with single gene therapy. CONCLUSION: In a rat model, a significant antitumoral effect against macroscopic multifocal liver metastases can be observed after retrovirus-mediated HSV1-TK and interleukin-2 gene transfer through the portal vein under total vascular exclusion of the liver, followed by ganciclovir administration. We believe that this well-tolerated and efficient therapeutic approach deserves clinical evaluation in patients with disseminated colorectal liver metastases.

Animals↗

PubMed2002

Biliary administration of naked DNA encoding Fas-Fc protein prevents acute liver failure in mice.

Acute liver failure (ALF) of infectious origin results from massive Fas-mediated hepatocyte apoptosis. To cure Fas-induced ALF in mice, we have designed a noninvasive procedure for intrahepatic transfer of a plasmid that encodes a molecule inhibiting Fas-Fas ligand interaction. For that purpose, naked pDNA encoding green fluorescent protein (GFP) or the Fas-Fc chimeric protein was transferred into mice by the biliary route. Ten percent of hepatocytes expressed GFP. After pFas-Fc transfer, about 40 ng of Fas-Fc protein per milliliter could be detected in sera from day 4 to day 28. Serum recombinant Fas-Fc could neutralize Fas-induced cell death in vitro. Furthermore, pFas-Fc biliary transfer efficiently protected mice against Fas-mediated ALF, because survival rates (p < 0.01), serum transaminase activities (p < 0.05), and histological data (p < 0.02) were improved versus control pTNFR-Fc-transfected mice. In conclusion, naked pDNA encoding Fas-Fc is efficiently expressed by hepatocytes after biliary gene transfer in mice. This method, devoid of virus-related risks, could be considered for the treatment of Fas-mediated ALF in humans.

Animals↗