title: Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir.
abstract: 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.
  
  
  CONCLUSIONS
  Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.
authors.forename: Romain
authors.initials: R
authors.lastname: Coriat
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Laurent
authors.initials: L
authors.lastname: Quinquis
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Hervé
authors.initials: H
authors.lastname: Lemaréchal
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.forename: Didier
authors.initials: D
authors.lastname: Borderie
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tréluyer
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Joel
authors.initials: J
authors.lastname: Coste
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D061605:Administration, Intravenous; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000401:mortality; D004492:Edetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006987:Hypesthesia / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D059225:Nociception / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D000077150:Oxaliplatin; D018384:Oxidative Stress; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011732:Pyridoxal Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid