Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo
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Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo. / Wei, Jiang; Freytag, Marcus; Schober, Yvonne; Nockher, Wolfgang A; Mautner, Viktor-Felix; Friedrich, Reinhard E; Manley, Paul W; Kluwe, Lan; Kurtz, Andreas.
in: PLOS ONE, Jahrgang 9, Nr. 10, 01.01.2014, S. e107760.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Nilotinib is more potent than imatinib for treating plexiform neurofibroma in vitro and in vivo
AU - Wei, Jiang
AU - Freytag, Marcus
AU - Schober, Yvonne
AU - Nockher, Wolfgang A
AU - Mautner, Viktor-Felix
AU - Friedrich, Reinhard E
AU - Manley, Paul W
AU - Kluwe, Lan
AU - Kurtz, Andreas
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0107760
DO - 10.1371/journal.pone.0107760
M3 - SCORING: Journal article
C2 - 25340526
VL - 9
SP - e107760
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 10
ER -