title: Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo.
abstract: Plexiform neurofibromas (PNFs) are benign nerve sheath tumors mostly associated with neurofibromatosis type 1. They often extend through multiple layers of tissue and therefore cannot be treated satisfactorily by surgery. Nilotinib is a tyrosine kinase inhibitor used to treat leukemia, with advantages over the prototype imatinib in terms of potency and selectivity towards BCR-ABL, and the DDR, PDGFR, and KIT receptor kinases. In this study, we compared efficacies of the two drugs on cultured cells of PNF in vitro and on xenografted tumor fragments on sciatic nerve of athymic nude mice. Xenografts were monitored weekly using a high resolution ultrasound measurement. Treatment with nilotinib at a daily dose of 100 mg/kg for four weeks led to a reduction of the graft sizesstd by 68±7% in the 8 treated mice, significantly more than the 33±8% reduction in the 8 untreated mice (P<0.05) and the 47±15% in the 7 mice treated with imatinib (P<0.05). The peak plasma nilotinib concentration 6.6±1.1 µM is within the pharmacological range of clinical application. Imatinib, but not nilotinib significantly hindered body weight increase of the mice and elevated cytotoxicity of mouse spleen cells (P<0.05). Our results suggest that nilotinib may be more potent than imatinib for treating PNFs and may also be better tolerated. Imatinib seems to have some off-target effect in elevating immunity.
authors.affiliation: Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Freytag
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Philipps University Marburg, Marburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schober
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Philipps University Marburg, Marburg, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Nockher
authors.affiliation: Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Department of Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Friedrich
authors.affiliation: Novartis Institute of Biomedical Research, Basel, Switzerland.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.affiliation: Laboratory for Tumor Genetics, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.affiliation: Berlin Brandenburg Center for Regenerative Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; Seoul National University, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul, Republic of Korea.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kurtz
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008819:Mice, Nude; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012583:Schwann Cells / Q000187:drug effects / Q000473:pathology; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib