Eugene J. Koay, Mark J. Truty, Vittorio Cristini, Ryan M. Thomas, Rong Chen, Deyali Chatterjee, Ya’an Kang, Priya R. Bhosale, Eric P. Tamm, Christopher H. Crane, Milind Javle, Matthew H. Katz, Vijaya N. Gottumukkala, Marc A. Rozner, Haifa Shen, Jeffery E. Lee, Huamin Wang, Yuling Chen, William Plunkett, James L. Abbruzzese, Robert A. Wolff, Gauri R. Varadhachary, Mauro Ferrari, Jason B. Fleming
Thomas O. Carpenter, Erik A. Imel, Mary D. Ruppe, Thomas J. Weber, Mark A. Klausner, Margaret M. Wooddell, Tetsuyoshi Kawakami, Takahiro Ito, Xiaoping Zhang, Jeffrey Humphrey, Karl L. Insogna, Munro Peacock
Ele Ferrannini, Elza Muscelli, Silvia Frascerra, Simona Baldi, Andrea Mari, Tim Heise, Uli C. Broedl, Hans-Juergen Woerle
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. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.
Romain Coriat, Jérôme Alexandre, Carole Nicco, Laurent Quinquis, Evelyne Benoit, Christiane Chéreau, Hervé Lemaréchal, Olivier Mir, Didier Borderie, Jean-Marc Tréluyer, Bernard Weill, Joel Coste, François Goldwasser, Frédéric Batteux
Ute E. Burkhardt, Ursula Hainz, Kristen Stevenson, Natalie R. Goldstein, Mildred Pasek, Masayasu Naito, Di Wu, Vincent T. Ho, Anselmo Alonso, Naa Norkor Hammond, Jessica Wong, Quinlan L. Sievers, Ana Brusic, Sean M. McDonough, Wanyong Zeng, Ann Perrin, Jennifer R. Brown, Christine M. Canning, John Koreth, Corey Cutler, Philippe Armand, Donna Neuberg, Jeng-Shin Lee, Joseph H. Antin, Richard C. Mulligan, Tetsuro Sasada, Jerome Ritz, Robert J. Soiffer, Glenn Dranoff, Edwin P. Alyea, Catherine J. Wu