The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis

Grichnik, James M.; Burch, James A.; Burchette, James L.; Shea, Christopher R.

doi:10.1016/s0923-1811(98)83583-4

Cited by 81 publications

(105 citation statements)

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“…This finding provides in vitro evidence of a critical role for SCF/KIT in the homeostasis and survival of human melanocytes. 3 The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk-2). Microphthalmia (Mi), a basic, helix-loop-helix, leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) play a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. 3,4 Case Reports Patient 1 was a 63-year-old African-American female who was diagnosed in August 1997 with CML and treated sequentially with hydroxyurea, interferon-␣ (IFN-␣) and cytarabine (Ara-C), and pegylated interferon. In November 2000, she developed clonal evolution with blast crises and treatment with imatinib mesylate was initiated at a dose of 600 mg daily.…”

Section: Matinib Mesylate (Gleevec [Sti-571]; Novartis Pharmaceuticalsmentioning

confidence: 99%

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Imatinib mesylate causes hypopigmentation in the skin

Tsao

Kantarjian

Cortes

et al. 2003

Cancer

140

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BACKGROUNDImatinib mesylate is a tyrosine kinase inhibitor that targets the BCR‐ABL protein in CML, c‐kit (KIT) and platelet‐derived growth factor receptors. In clinical trials with imatinib mesylate, common side effects of nausea, emesis, diarrhea, periorbital edema, fluid retention, and myelosuppression have been documented.METHODSIn this case series, the authors describe unique clinical findings of skin hypopigmentation in six patients with CML who were treated with imatinib mesylate.RESULTSMost patients developed onset of skin hypopigmentation within the first month of treatment and all of the patients experienced additional drug toxicity. Despite patient susceptibility to toxicity, the presence of hypopigmentation did not appear to predict leukemic cell response or clinical outcome. All six patients established a hematologic response but only two patients had a complete cytogenetic response. Imatinib mesylate induced hypopigmentation also appeared to be reversible and potentially dose related.CONCLUSIONSkin hypopigmentation is a benign side effect from imatinib mesylate treatment that appears to be reversible upon discontinuation or dose reduction. Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation. The signal transduction mechanism currently is believed to involve SCF ligand binding of KIT and downstream activation of MAP kinase (Erk‐2). Microphthalmia (Mi), a basic helix‐loop‐helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73). Once phosphorylated, Mi transactivates the tyrosine pigmentation gene promoter and affects pigment production. Cancer 2003. © 2003 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Section: Matinib Mesylate (Gleevec [Sti-571]; Novartis Pharmaceuticalsmentioning

confidence: 99%

Imatinib mesylate causes hypopigmentation in the skin

Tsao

Kantarjian

Cortes

et al. 2003

Cancer

140

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“…80 Recent data suggest that c-KIT has a major role in melanogenesis, melanocyte homeostasis and ultraviolet B-induced pigmentation. 81 Myelosuppression. c-KIT is essential for the development of normal blood cells, melanocytes and mast cells.…”

Section: C-kit Inhibition: Dermatologic Toxicity Myelosuppression Anmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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“…3 For melanocyte identi®cation, 4-mm sections were cut and stained immunohistochemically with monoclonal antibody to melanocytes (monoclonal antibodies to NKI/beteb, Monosan q , UK) using the ABC (avidin biotin complex) method. 4,5 For a more standardized evaluation, all stains were performed on the same day, under the same conditions, and by the same technician.…”

Section: Melanin and Melanocyte Stainingmentioning

confidence: 99%