Center for Research on Angiogenesis Inhibitors

Paris, France

Center for Research on Angiogenesis Inhibitors

Paris, France

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Coriat R.,University of Paris Descartes | Coriat R.,Center for Research on Angiogenesis Inhibitors | Alexandre J.,University of Paris Descartes | Alexandre J.,Center for Research on Angiogenesis Inhibitors | And 14 more authors.
Journal of Clinical Investigation | Year: 2014

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≤2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≤2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Universite Paris Descartes, Ministere de la Recherche et de lEnseignement Superieur, and Assistance Publique-Hopitaux de Paris.


Boudou-Rouquette P.,Center for Research on Angiogenesis Inhibitors | Ropert S.,Center for Research on Angiogenesis Inhibitors | Mir O.,Center for Research on Angiogenesis Inhibitors | Coriat R.,Center for Research on Angiogenesis Inhibitors | And 8 more authors.
Oncologist | Year: 2012

Background. Sorafenib displays major interpatient phar- macokinetic variability. It is unknown whether the phar- macokinetics of sorafenib influence its toxicity. Methods. We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive pa- tients with cancer, as well as their relationship with biolog- ical, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. Results. For 83 patients (median age, 62 years; range, 21-84 years), median sorafenib 12-hour area under the curve (AUC0-12) was 52.8 mg · h/L (range: 11.8-199.6). A total of 51 patients (61%) experienced grade 3-4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0-12preceding grade 3-4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC0-12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin re- actions significantly decreased over time. Conclusion. Sorafenib AUC0-12decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentra- tions may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression. © AlphaMed Press.


Coriat R.,Laboratoire dImmunologie | Coriat R.,University of Paris Descartes | Coriat R.,Center for Research on Angiogenesis Inhibitors | Nicco C.,Laboratoire dImmunologie | And 15 more authors.
Molecular Cancer Therapeutics | Year: 2012

Sorafenib is presently the only effective therapy in advanced hepatocellular carcinoma (HCC). Because most anticancer drugs act, at least in part, through the generation of reactive oxygen species, we investigated whether sorafenib can induce an oxidative stress. The effects of sorafenib on intracellular ROS production and cell death were assessed in vitro in human (HepG2) and murine (Hepa 1.6) HCC cell lines and human endothelial cells (HUVEC) as controls. In addition, 26 sera from HCC patients treated by sorafenib were analyzed for serum levels of advanced oxidation protein products (AOPP). Sorafenib significantly and dose-dependently enhanced in vitro ROS production by HCC cells. The SOD mimic MnTBAP decreased sorafenib-induced lysis of HepG2 cells by 20% and of Hepa 1.6 cells by 75% compared with HCC cells treated with 5 mg/L sorafenib alone. MnTBAP significantly enhanced by 25% tumor growth in mice treated by sorafenib. On the other hand, serum levels of AOPP were higher in HCC patients treated by sorafenib than in sera collected before treatment (P < 0.001). An increase in serum AOPP concentration ≥0.2 μmol/L chloramine T equivalent after 15 days of treatment is a predictive factor for sorafenib response with higher progression free survival (P < 0.05) and overall survival rates (P < 0.05). As a conclusion, sorafenib dose-dependently induces the generation of ROS in tumor cells in vitro and in vivo. The sera of Sorafenib-treated HCC patients contain increased AOPP levels that are correlated with the clinical effectiveness of sorafenib and can be used as a marker of effectiveness of the drug. ©2012 AACR.


Mir O.,Center for Research on Angiogenesis Inhibitors | Mir O.,University of Paris Descartes | Alexandre J.,Center for Research on Angiogenesis Inhibitors | Coriat R.,Center for Research on Angiogenesis Inhibitors | And 7 more authors.
Investigational New Drugs | Year: 2012

Background Bevacizumab is a humanized IgG1 monoclonal antibody against VEGF. Because infusionrelated hypersensitivity reactions (HSRs) are a concern with monoclonal antibodies, initial phase 1 trials used a 90-, 60-, then 30-min initial infusion sequence. We evaluated the impact of a shortened bevacizumab infusion (10 min) on toxicity in nonsmall cell lung cancer (NSCLC) patients. Patients and methods Consecutive patients with stage IV NSCLC eligible for anti-VEGF therapy received a platinum doublet plus bevacizumab 7.5 mg/kg infused over 10 min, every 3 weeks, in the outpatient setting. Blood pressure was monitored at home twice daily, and other toxicities (HSRs and proteinuria) were monitored at each treatment administration. Results Bevacizumab was given as a 10 min infusion in 55 patients (group A), and using the standard sequence in another 36 patients (group B). Hypertension (grade ≥2) was observed in 18/55 (32.7%) patients in group A and 13/36 (38.9%) patients in group B (p=0.77). Similarly, no difference was seen regarding the incidence of grade ≥2 proteinuria (12.7% vs. 19.4%, p=0.39), arterial thromboembolic events (0 in each group) or venous thromboembolic events (1.8% vs. 8.3%, p=0.29). Conclusions Our data suggest that bevacizumab 7.5 mg/kg can be safely infused over 10 min in unselected NSCLC patients despite their cardio-vascular and respiratory comorbidities, saving time for both patients and caregivers. © Springer Science+Business Media, LLC 2011.


Coriat R.,Center for Research on Angiogenesis Inhibitors | Coriat R.,Teaching Hospital Cochin | Coriat R.,University of Paris Descartes | Gouya H.,University of Paris Descartes | And 22 more authors.
PLoS ONE | Year: 2011

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients. © 2011 Coriat et al.


PubMed | Center for Research on Angiogenesis Inhibitors
Type: Controlled Clinical Trial | Journal: PloS one | Year: 2011

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.

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