The skeletal effects of the tyrosine kinase inhibitor nilotinib

O'Sullivan, Susannah; Lin, Jian-Ming; Watson, Maureen; Callon, Karen E.; Tong, Pak Cheung; Naot, Dorit; Horne, Anne; Aati, Opetaia; Porteous, Fran; Gamble, Greg; Cornish, Jillian; Browett, Peter; Grey, Andrew

doi:10.1016/j.bone.2011.04.014

Cited by 37 publications

(40 citation statements)

References 37 publications

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“…Полагают, что терапия с применением ингибиторов протеинтирозинкиназы -иматиниба и нилотиниба вызывает развитие гипофосфатемии вследствие ингибирования образования как остеобластов, так и остеокластов, снижения содержания кальция в сыворотке крови, стимулируя развитие ВГПТ [42][43][44].…”

Section: остеомаляция на фоне гипофосфатемииunclassified

Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis

Golounina¹,

Рунова²,

Fadeyev³

2020

Osteopor Bone Dis

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Osteoporosis is the most common cause of low bone mineral density (BMD) and low-traumatic fractures in adults. However, differential diagnosis should also consider other causes of decreased BMD, including osteomalacia, as treatment for these conditions vary significantly. Osteomalacia is a systemic disorder characterized by decrease in bone strength due to of excessive accumulation of non-mineralized osteoid and uncoupling between bone matrix formation and mineralization. Osteomalacia in adults mostly develops due to severe vitamin D deficiency of any etiology, less often along with kidney pathology, mesenchymal tumors secreting fibroblast growth factor 23 or hereditary metabolic bone diseases. Clinical symptoms of osteomalacia are nonspecific and mostly manifest by generalized diffuse bone pain, muscle weakness, skeletal deformities and often go unnoticed at initial stage of the disease. Histomorphometric examination is the most accurate method of the diagnosis, which allows assessment of bone formation rate and calcification. The utmost priority of the treatment of osteomalacia of any etiology is the elimination of vitamin D deficiency, hypocalcemia, hypophosphatemia and prevention of bone deformities progression and muscle hypotension.

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Section: остеомаляция на фоне гипофосфатемииunclassified

Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis

Golounina¹,

Рунова²,

Fadeyev³

2020

Osteopor Bone Dis

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“…Moreover, studies on the effects of nilotinib on bone cells in Ph + patients receiving nilotinib for treatment of CML have demonstrated that nilotinib potently inhibited osteoblast proliferation through inhibition of the platelet-derived growth factor (PDGFR). Furthermore, inhibition of c-Abl could contribute to the growth inhibition of CFCs by TKIs since antisense strategies have demonstrated that inhibition of c-Abl leads to the accumulation of CD34 + cells in G 0 /G 1 and to inhibition of CFU-GM formation [28], [29]. Our results confirm also the results of Jorgensen and colleagues which showed that the predominant effect of imatinib and nilotinib on CD34 + CML cells is anti-proliferative rather than pro apoptotic.…”

Section: Discussionmentioning

confidence: 99%

Imatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells

et al. 2012

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BackgroundThe availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34+ cells.Design and MethodsAfter a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice.ResultsTKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34+ cell cycle entry. Adhesion of CD34+ cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT.ConclusionsThese data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.

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“…Nilotinib and CEP-751 may be added to the second family. Nilotinib potently inhibited osteoblast proliferation [56] . While nilotinib inhibits numerous RTKs (KIT, EPHA3, EPHA8, DDR1, DDR2, PDGFRB), its effects may be associated with the inhibition of PDGFR [65] .…”

Section: Rtks In Oncologymentioning

confidence: 99%

Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers

Ségaliny¹,

Gabriel²,

Heymann³

et al. 2015

Journal of Bone Oncology

125

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Bone cancers are characterised by the development of tumour cells in bone sites, associated with a dysregulation of their environment. In the last two decades, numerous therapeutic strategies have been developed to target the cancer cells or tumour niche. As the crosstalk between these two entities is tightly controlled by the release of polypeptide mediators activating signalling pathways through several receptor tyrosine kinases (RTKs), RTK inhibitors have been designed. These inhibitors have shown exciting clinical impacts, such as imatinib mesylate, which has become a reference treatment for chronic myeloid leukaemia and gastrointestinal tumours. The present review gives an overview of the main molecular and functional characteristics of RTKs, and focuses on the clinical applications that are envisaged and already assessed for the treatment of bone sarcomas and bone metastases.

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The skeletal effects of the tyrosine kinase inhibitor nilotinib

Cited by 37 publications

References 37 publications

Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis

Osteomalacia in practice of endocrinologist: etiology, pathogenesis, differential diagnosis with osteoporosis

Imatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells

Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers

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