Hair Depigmentation Research Articles

Stem cell factor–KIT signalling plays a pivotal role in regulating pigmentation in mammalian hair

Hair greying is one of the most distinct but least comprehended features of senescence. The signalling of stem cell factor (SCF) and its receptor KIT has been documented to regulate essential roles in the maintenance of embryonic melanocyte lineages and postnatal cutaneous melanogenesis, although little is known about its detailed mechanisms in postnatal hair pigmentation. To address this, anagen human hair follicles and C57BL/6 murine pelage were analysed in this study. Molecular biological analyses of murine follicular skin indicated a significant increase of membrane-bound SCF expression, reaching its peak 8-16 days after anagen induction in concert with the escalation of cutaneous tyrosinase activity and corresponding pigmentation. Administration of KIT-neutralizing antibody abolished MITF and tyrosinase expressions, resulting in a reversible hair depigmentation in murine regenerated hair and human hair organ culture. Quantitative RT-PCR of human hair follicles indicated that KIT expression as well as the expression of several melanogenic factors, including MITF, was significantly lower in unpigmented than in pigmented follicles. Taken together, these data revealed a pivotal role of SCF-KIT signalling in the maintenance of human hair follicle melanogenesis during the anagen cycle and its involvement in physiological ageing of the hair follicle pigmentary unit.

Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition

Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition

Continuous MEK inhibition by AZD6244 (ARRY-142886) results in exhaustion of the cutaneous keratinocytic stem cell pool and resembles senescence driven skin aging

9075 Background: The Raf/MEK/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation, and is associated with cutaneous toxicities similar to EGF targeting molecules but can also induce depigmentation. Methods: 28 patients (pts) with unresectable melanoma stage III/IV were randomized to temozolomide (TMZ 200mg/m2) or AZD6244 (100 mg po bid). 13 pts received AZD6244 initially, and 9 pts AZD6244 following tumor progression with TMZ. Acute and chronic skin reactions were documented and lesion biopsies were compared to matched controls in normal skin. Immunohistochemistry (p53, Ki67, pancytokeratin) was performed. Results: 19/22 (86,3%) AZD6244-treated pts presented with cutaneous eruptions. 17 pts (77,2%) developed acute papulopustular rash in seborrhoic regions within the first treatment weeks. Chronic skin changes (> 6–8 weeks) included xerosis, paronychia and pulpitis sicca, which is similar to that observed with EGFR-inhibition. In addition, we observed hair depigmentation and vitiligo correlating with the AZD6244 treatment period. Hair abnormalities such as nonscarring alopecia, trichomegaly of the eyebrows, facial hypertrichosis and thinning of the hair as seen with EGFR-Inhibitors were not observed. Histology of acute skin lesions revealed apoptotic keratinocytes (p53 positive) and destruction of the adnexal structures by neutrophilic infiltrates, reduced expression of cytokeratins and a shift of the proliferation (Ki67) from basal to the suprabasal keratinocytes reflecting self amplifying cells. Chronic lesions revealed a reduced stratum corneum, thinning of the epidermal cell layers with apoptotic keratinocytes and focal infiltrates mainly of neutrophils and occasional lymphocytes. The number of melanocytes was not reduced. Conclusions: The clinical presentation of AZD6244 associated skin reactions partly overlaps with those observed upon EGFR-Inhibition. Additionally melanocytic function is affected. We postulate that continuous MEK inhibition by AZD6244 results in exhaustion of the cutaneous keratinocytic stem cell pool thus resembling skin senescence. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca Oncology

Photoepilation

The field of dermatological laser medicine consists of four main areas: therapy for blood vessels, therapy for pigmented lesions, ablation of tissue, and photoepilation. The first tests were carried out in 1993, and since 1996 there has been a growing demand for "permanent hair removal." This strong demand and the rapid development of devices call for extensive knowledge in terms of current technical innovation or affirmation of proven procedures. This article gives a general survey of the different systems that can be used for "permanent hair removal" [ruby laser, alexandrite laser, diode, Nd:YAG laser, so-called intense pulsed light (IPL) systems, and combined radio frequency/IPL systems], including their inherent advantages and disadvantages. Physical and biological aspects necessary for photoepilation are pointed out. Furthermore, we emphasize new methods concerning removal of depigmented and therapy-resistant hair, as well as the treatment of female patients with polycystic ovary syndrome.

Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT)

5031 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth & inhibits angiogenesis. This Phase II RDT determined effects of pazopanib on tumor growth in patients with adv/met RCC after 12 wks of treatment. Methods: Cytokine naïve and refractory (failed 1 prior cytokine or bevacizumab-containing regimen) patients with adv/met RCC, ECOG 1–2, were enrolled. Pazopanib 800 mg po qd was administered. Response (RECIST) assessed at wk 12: SD patients randomized to continue pazopanib or placebo (blinded); PR/CR patients continued pazopanib. Interim analysis (first 60 patients) endpoints: % randomized (SD) and % CR/PR at wk 12. Futility boundary was based on a randomization rate of <40%. Safety was analyzed in enrolled patients (n=161) at the time of interim analysis. Results: In the first 60 patients, response at wk 12 by independent review: PR in 24 (40%); SD in 25 (42%); PD in 5 (8%); unknown response in 2 (3%); and withdrawal prior to wk 12 (reasons other than PD/AE) in 4 (7%). 27 (45%) patients were randomized based on investigator review at wk 12. Total disease control rate was 82% (PR + SD). 67% of patients were treatment naïve, 33% had failed one prior treatment regimen (23% cytokine, 8% bevacizumab, 2% both). Most common AEs/lab abnormalities in all patients (n=161; 71% M, 29% F; mean 60.3 yrs; 81% Caucasian) were ALT/AST elevations, diarrhea, fatigue, nausea, hair depigmentation, & hypertension. Gr 3/4 AEs occurred in 26% of patients; most common were hypertension (8%) & ALT elevation (8%). One patient had Gr 5 AE due to large intestinal perforation. AEs led to discontinuation in 5% of patients. Conclusions: Interim analysis of this Ph II study demonstrated that pazopanib treatment resulted in a PR rate at wk 12 of 40% among patients with adv/met RCC and an acceptable toxicity profile. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of randomization to placebo. Patients without PD were offered continued treatment with pazopanib beyond wk 12. At the time of publication, efficacy and safety data will be available for all 225 patients. [Table: see text]

Hair Depigmentation During Chemotherapy With a Class III/V Receptor Tyrosine Kinase Inhibitor

Hair pigmentation is regulated by several factors including the interaction of the ligand stem cell factor (SCF) with its class III receptor tyrosine kinase, c-kit. An interruption of SCF/c-kit signal transduction results in hair depigmentation. A 69-year-old white woman developed hair depigmentation and fine-textured hair while being treated with the phase I chemotherapeutic agent GW786034, a class III/V receptor tyrosine kinase inhibitor. Discontinuation of therapy resulted in a reversal of these hair changes. Treatment with oral GW786034 resulted in reversible hair depigmentation and change in hair growth rate and texture, which were most likely due to an incomplete inhibition of SCF/c-kit signaling, although the exact mechanism is unknown. It would be intriguing to investigate topical tyrosine kinase inhibitors as a treatment for unwanted body hair.

A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently

3088 Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of > 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of < 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib. [Table: see text]

Basic Fibroblast Growth Factor Promotes Melanocyte Migration via Increased Expression of p125FAK on Melanocytes

Vitiligo is an acquired pigmentary disorder characterized by depigmentation of skin and hair. Melanocyte migration is an important event in re-pigmentation of vitiligo. We have demonstrated that narrow-band ultraviolet B (UVB) irradiation stimulated cultured keratinocytes to release a significant amount of basic fibroblast growth factor (bFGF). Furthermore, narrow-band UVB enhanced migration of melanocytes via increased expression of phosphorylated focal adhesion kinase (p125(FAK)) on melanocytes. The aim of this study was to investigate the effect of recombinant human bFGF (rhbFGF) on melanocyte migration. The relationship between the expression of p125(FAK) and melanocyte migration induced by rhbFGF was also studied. Our results demonstrated that rhbFGF significantly enhanced migration of melanocytes and p125(FAK) expression on melanocytes. Herbimycin A, a potent p125(FAK) inhibitor, effectively abolished rhbFGF-induced melanocyte migration. The combined results indicated that p125(FAK) plays an important role in the signal transduction pathway of melanocyte migration induced by bFGF.

Cochlear implantation in children with Waardenburg syndrome

Waardenburg syndrome is an autosomal-dominant trait resulting from mutations occurring in different genes. It is often characterized by varying degrees of: congenital hearing loss; dystopia canthorum; synophrys; broad nasal root; depigmentation of hair (white forelock), skin or both; and heterochromic or hypochromic irides. A retrospective case study was done to assess speech perception, speech production, general intelligence and educational setting in six profoundly hearing-impaired children with Waardenburg syndrome (four with type I, one with type II and one with type III) ranging in age from two years to 14 years, seven months (mean = six years, six months). None of the patients had malformation of the cochlea and were implanted using Nucleus 22/24 and Med-el combi40+. Five out of the six cases were of average intelligence and one had a borderline intelligence quotient. The follow-up period ranged from one year, 10 months to six years, six months (mean = three years, six months) after implantation. The evaluation of auditory perception in patients was accomplished using the Persian Auditory Perception Test for the Hearing-Impaired, a Persian Spondee words test and the Categories of Auditory Performance Index. The Speech Intelligibility Rating test was used to evaluate speech production ability. All the patients' speech perception and speech intelligibility capabilities improved considerably after receiving the implants, and they were able to be placed in regular educational settings. Patients used their cochlear-implant devices whenever awake, implying that they benefitted from the devices. We suggest that any further expansion of cochlear-implantation criteria in children include those with Waardenburg syndrome.

FK506 promotes melanocyte and melanoblast growth and creates a favourable milieu for cell migration via keratinocytes: possible mechanisms of how tacrolimus ointment induces repigmentation in patients with vitiligo

Vitiligo is an acquired pigmentary disorder characterized by depigmentation of skin and hair. As the pathogenesis of this disease is still obscure, the treatment of vitiligo has generally been unsatisfactory and often disappointing. Topical tacrolimus (FK506) ointment has recently been added to the armamentarium against this pigmentary disorder. Despite its clinical efficacy, the underlying mechanisms of how topical tacrolimus induces repigmentation in vitiligo have rarely been investigated. As tacrolimus ointment is applied directly to the skin, its impact on keratinocytes (KCs) requires thorough investigation. To investigate the effects of FK506 on melanocyte (MC) and melanoblast (MB) growth via KCs. Cultured MCs and MBs were treated with supernatant of KC cultures conditioned with various concentrations of FK506. The impact of supernatant on MCs and MBs was assessed in terms of its effect on MC/MB proliferation, melanin formation and cell migration. The activities of matrix metalloproteinase (MMP)-2 and MMP-9, known for their influence on cell migration, were evaluated. The concentrations of MC/MB growth factors in the KC supernatant were also determined. Results demonstrated that proliferation of both MCs and MBs was significantly enhanced by FK506-treated KC supernatant. In addition, the concentration of stem cell factor in KC supernatant increased dose-dependently with FK506 treatment. The supernatant from FK506-treated KC culture showed a significant increase in MMP-9 activity. Our study provides in vitro evidence demonstrating that direct interaction between FK506 and KCs creates a favourable milieu for MC growth and migration. Furthermore, our findings provide a possible mechanism explaining how tacrolimus ointment induces repigmentation in patients with vitiligo.

Síndrome literatura uveodermatológica:revisão de literatura

Objetivo: Revisar os principais aspectos etiológicos, epidemiológicos, diagnósticos e terapêuticos da síndrome uveodermatológica. Fontes Pesquisadas: Foi realizado levantamento nas bases de dados CAB e PUBMED e nos acervos das bibliotecas das Faculdades de Medicina e Medicina Veterinária da Universidade Federal de Minas Geraise da Biblioteca da Universidade Federal de Lavras, pelo período retrospectivo de 35 anos. Síntese dos Dados: Asíndrome uveodermatológica é uma doença multissistêmica, auto-imune contra os melanócitos e semelhante à síndrome Vogt-Koyanagi-Harada em humanos. Os sinais clínicos mais evidentes são uveíte e glaucoma bilateral, além da despigmentação de pele e pelos. O manejo consiste em cicloplégicos, anti-inflamatórios não-esteroidais, corticosteróides e fármacos imunossupressores. O prognóstico é reservado a longo prazo. Conclusões: A síndrome uveodermatológica apresenta incidência crescente e é de grande importância na oftalmologia veterinária. O manejo precoce e correto é necessário para se evitar a perda da visão.

Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors

3012 Background: GW786034 is a tyrosine kinase inhibitor of VEGFR-1,-2 and -3, PDGFR-α and -β, and c-kit. Plasma trough concentrations above ∼ 18 μg/mL were required for optimal anti-tumor and anti-angiogenic activity in animal models. Methods: Pts with solid tumors were enrolled in an ongoing Phase I study. Safety (including daily BP monitoring), single- and multiple-dose PK, biomarkers, and clinical activity were evaluated. Response was assessed by RECIST. Results: 43 pts were enrolled in the dose escalation phase at doses ranging from 50 mg 3 times weekly to 2000 mg daily (qd) in 11 cohorts. Mean half-life was ∼ 35 hrs. Accumulation of 1.5 - 3 fold and Cmax/Cmin of ∼ 2 were observed at steady-state. Maximal exposure with trough concentrations (C24) > 18 μg/mL were observed after doses ≥ 800 mg qd. MTD was not achieved. The most frequent drug related AEs were NCI CTC2, Gr 1 and 2: nausea (Gr 1/2 n=15, Gr 3 n=1), diarrhea (Gr 1/2 n=15), fatigue (Gr 1/2 n=12, Gr 3 n=1), HTN (Gr 1/2 n=6, Gr 3 n=6), anorexia (Gr 1/2 n=12), and vomiting (Gr 1/2 n=9, Gr 3 n=1). Hair depigmentation was observed (n=6/14) at doses of ≥ 800 mg. The greatest magnitude in BP change was observed at 800 mg and correlated with C24 of > 20 μg/mL. HTN was amenable to treatment and was reversible upon cessation of GW786034. No pts were withdrawn from study solely due to HTN. One of 3 pts treated at 2000 mg qd developed Gr 3 fatigue (DLT). Tumor shrinkage (minimal response) was observed in all 3 pts with renal cell cancer treated at ≥ 800 mg qd and in one pt with Hurthel cell tumor. Six additional pts (melanoma n=1, sarcoma n=3, lung n=1, neuroendocrine n=1) remained on study for ≥ 6 mos with SD. Conclusion: GW786034 was generally well tolerated with preliminary evidence of anti-tumor activity in cancer patients. HTN and hair depigmentation were indicative of VEGFR and c-kit modulation. Two dose cohorts (800 mg qd and 300 mg bid) are being expanded. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

Fallberichte

After application of bimatoprost containing eye drops for four weeks, a 72 year-old patient, suffering from glaucoma, developed hyperpigmentation and hypertrichosis of the eyelids. These symptoms can be seen in 1-10% of the patients as side effects in local therapy with bimatoprost, a prostaglandin analogue. The changes persist for varying periods of time but are reversible. Although prostaglandin analogues are sometimes more effective in the reduction of the intraocular pressure than beta-adrenoreceptor blocking agents, they remain second-line choices because of their side effects. This case report is meant to re-stimulate interest in the as yet obscure role of prostaglandins in hair biology, in clarifying the underlying mechanisms, and in exploring the possible therapeutic use of prostaglandin analogues in the management of hair loss (e.g. in androgenetic alopecia) or hair depigmentation (e.g. poliosis, canities).

Keratinocyte stem cells, label-retaining cells and possible genome protection mechanisms.

Stem cells are the crucial cells upon which the entire tissue is dependent. Here we define and discuss what is meant by and known about keratinocyte stem cells. One way in which these cells have been studied is by their ability to retain radioactivity labelled thymidine for long periods of time (label retaining cells, LRCs). The underlying mechanism has been assumed in the past to be slow cycling but a more likely explanation is the selective segregation of old and new DNA strands (Cairns's hypothesis). Experiments in the small intestine indicate that the stem cells here are selectively sorting their DNA and becoming LRCs. A possible role for p53 in stem cell biology is presented.

Alopecia totalis incognito

We report an 11‐year‐old boy with a strong family history of alopecia areata who initially developed alopecia areata with a single circular patch of hair loss on the scalp with exclamation mark hairs at the periphery, which evolved over time into alopecia totalis and then into a novel pattern of hair growth with fine depigmented hair, uniformly 5 mm in length. The hair has not grown any longer over a 48‐month follow‐up period. Scalp biopsies from the occipital scalp demonstrate dense peribulbar lymphocytic infiltrate and uniform miniaturized secondary vellus hairs. This previously undescribed pattern of alopecia areata is remarkable for total lack of alopecia.

Clinical and histopathological characterization of cutaneous melanomas in the melanoblastoma-bearing Libechov minipig model.

Spontaneous animal tumors appear to be highly suitable models to study human oncology and cancer therapy. The aim of this study was to characterize the clinical and histological features of hereditary melanocytic lesions found in the French herd of melanoblastoma-bearing Libechov minipigs (MeLiM) and their Duroc crossbreeds. Clinically, we discriminated between three types of melanocytic skin lesions, which offer a lesion continuum from lentigo to metastatic melanomas. More than 70% of these lesions appear on piglets before they are 3 months old and preferentially on homogeneous black coat piglets. The incidence of melanoma reaches 50% in MeLiM. Most of the highly invasive melanomas regressed spontaneously in the first year of the piglet's life and the regression was followed by hair, skin and iris depigmentation. A histopathological study was conducted according to the human melanoma classification. Except for lentigo maligna, we observed the three main types of human melanoma in swine [superficial spreading melanoma (SSM), nodular or unclassified melanoma] with an excess of SSM (59-67%). The histological events leading to total spontaneous regression are chronologically described. The genetic predisposition, the high incidence of melanoma, the clinical and histopathological features similar to the human disease and the high rate of spontaneous regression offer an opportunity to use this model for studying genetic events controlling melanoma development and regression and the biological mechanisms involved in oncogenesis and anti-cancerous self-defense.

Cancer Treatment Changes Hair Color

Kinases are appealing targets in the battle against cancer because in many cases their activity is increased in the cancerous cells or their activity is required for such cancer cell survival processes as the growth of new blood vessels into the tumor. KIT is a receptor tyrosine kinase that is one of the kinases inhibited by drugs already in the clinic, such as Gleevec, and is one target of other kinase inhibitors still in development. KIT and its ligand stem cell factor are known to be essential for proper hair pigmentation, and mutations in their encoding genes are associated with various hair pigmentation phenotypes. Moss et al. reported that mice receiving oral SU11248, a kinase inhibitor undergoing Phase I clinical trials, or injections of an antibody that neutralizes KIT activity exhibited dose-dependent loss of hair pigmentation. The depigmentation was reversible with cessation of treatment. Histochemical analysis demonstrated that there was no loss of KIT-positive melanocytes in the hair follicles. Furthermore, human subjects in the Phase I trial also reported hair depigmentation patterns that correlated with the duration of treatment. Thus, hair depigmentation may serve as a noninvasive readout of the effectiveness of kinase inhibitors for the KIT receptor. K. G. Moss, G. C. Toner, J. M. Cherrington, D. B. Mendel, A. D. Laird, Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J. Pharmacol. Exp. Ther. 307 , 476-480 (2003). [Abstract] [Full Text]

Cancer Treatment Changes Hair Color

Kinases are appealing targets in the battle against cancer because in many cases their activity is increased in the cancerous cells or their activity is required for such cancer cell survival processes as the growth of new blood vessels into the tumor. KIT is a receptor tyrosine kinase that is one of the kinases inhibited by drugs already in the clinic, such as Gleevec, and is one target of other kinase inhibitors still in development. KIT and its ligand stem cell factor are known to be essential for proper hair pigmentation, and mutations in their encoding genes are associated with various hair pigmentation phenotypes. Moss et al. reported that mice receiving oral SU11248, a kinase inhibitor undergoing Phase I clinical trials, or injections of an antibody that neutralizes KIT activity exhibited dose-dependent loss of hair pigmentation. The depigmentation was reversible with cessation of treatment. Histochemical analysis demonstrated that there was no loss of KIT-positive melanocytes in the hair follicles. Furthermore, human subjects in the Phase I trial also reported hair depigmentation patterns that correlated with the duration of treatment. Thus, hair depigmentation may serve as a noninvasive readout of the effectiveness of kinase inhibitors for the KIT receptor.K. G. Moss, G. C. Toner, J. M. Cherrington, D. B. Mendel, A. D. Laird, Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J. Pharmacol. Exp. Ther. 307, 476-480 (2003). [Abstract] [Full Text]

Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans.

Deregulated activation of the KIT receptor tyrosine kinase has been implicated in several human cancers and in inflammation, making it an attractive target for therapeutic intervention. Conversely, deficiencies in KIT signaling have been implicated in human and animal hair pigmentation disorders, reflecting a role for KIT in the development and function of melanocytes. The goal of this study was to explore the potential utility of hair depigmentation as a biological readout for systemic inhibition of KIT by SU11248 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide), an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity through targeting platelet-derived growth factor receptors, vascular endothelial growth factor receptors, KIT, and FLT3. Oral SU11248 treatment induced dose-dependent depigmentation of newly regrown hair in depilated C57BL/6 mice. Similar effects were seen after administration of a KIT-neutralizing antibody. SU11248-induced hair depigmentation was reversible with cessation of treatment. Histological and immunohistochemical evaluation of mouse skin samples supported these observations and revealed that SU11248 has no effect on levels of KIT-positive melanocytes associated with hair follicles, indicating that the inhibitory effect is at the level of melanocyte function rather than their development/survival. Similar hair depigmentation has been noted in several cancer patients receiving SU11248 in phase I trials. Strikingly, patient scalp hair exhibits bands of depigmentation and pigmentation that correspond, respectively, to periods of treatment and dosing rest periods. These data demonstrate that hair pigmentation can serve as a dose-dependent, dynamic, biological readout for KIT inhibition in mice, and, apparently, in humans.

Treatment with the novel drug SU 11248* appears to be associated with hair depigmentation,

Treatment with the novel drug SU 11248* appears to be associated with hair depigmentation,