A New Strategy for Modulating Chemotherapy-Induced Alopecia, Using PTH/PTHrP Receptor Agonist and Antagonist

Peters, Eva M.J.; Foitzik, Kerstin; Paus, Ralf; Ray, Swapna; Holick, Michael F.

doi:10.1046/j.0022-202x.2001.01410.x

Cited by 56 publications

(56 citation statements)

References 31 publications

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“…PTHrP regulates the rate of keratinocyte differentiation (70), and PTHrP antagonists accelerate anagen and enhance hair growth in mice (71). Thus, PTHrP may be a tonic inhibitor of hair growth.…”

Section: Resultsmentioning

confidence: 99%

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Hsieh

Sisk

Jurutka

et al. 2003

Journal of Biological Chemistry

207

201

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Both the vitamin D receptor (VDR) and hairless (hr) genes play a role in the mammalian hair cycle, as inactivating mutations in either result in total alopecia. VDR is a nuclear receptor that functions as a ligand-activated transcription factor, whereas the hairless gene product (Hr) acts as a corepressor of both the thyroid hormone receptor (TR) and the orphan nuclear receptor, ROR␣. In the present study, we show that VDR-mediated transactivation is strikingly inhibited by coexpression of rat Hr. The repressive effect of Hr is observed on both synthetic and naturally occurring VDR-responsive promoters and also when VDR-mediated transactivation is augmented by overexpression of its heterodimeric partner, retinoid X receptor. Utilizing in vitro pull down methods, we find that Hr binds directly to VDR but insignificantly to nuclear receptors that are not functionally repressed by Hr. Coimmunoprecipitation data demonstrate that Hr and VDR associate in a cellular milieu, suggesting in vivo interaction. The Hr contact site in human VDR is localized to the central portion of the ligand binding domain, a known corepressor docking region in other nuclear receptors separate from the activation function-2 domain. Coimmunoprecipitation and functional studies of Hr deletants reveal that VDR contacts a C-terminal region of Hr that includes motifs required for TR and ROR␣ binding. Finally, in situ hybridization analysis of hr and VDR mRNAs in mouse skin demonstrates colocalization in cells of the hair follicle, consistent with a hypothesized intracellular interaction between these proteins to repress VDR target gene expression, in vivo.Nuclear receptors comprise a family of ligand-activated transcription factors that coordinate physiological and developmental processes by regulating specific changes in gene expression (1, 2). The vitamin D receptor (VDR) 1 mediates signaling by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and is a member of the thyroid hormone/retinoic acid receptor subfamily of nuclear receptors that heterodimerize with the retinoid X receptor (RXR) on direct repeat hormone-responsive elements in the promoters of regulated genes (3, 4). Binding of liganded VDR⅐RXR to a vitamin D-responsive element (VDRE) in target genes such as osteocalcin, osteopontin, and vitamin D 24-hydroxylase (CYP24) is accompanied by the recruitment of coactivator proteins (5). VDR coactivators such as steroid receptor coactivator-1 (6), NCoA-62 (7), and vitamin D receptor interacting protein 205 (8) stimulate transcriptional activation by facilitating chromatin remodeling and/or attraction of RNA polymerase II. Although some unliganded nuclear receptors (thyroid hormone and retinoic acid receptors) can mediate repression through association with corepressors such as nuclear receptor corepressor (N-CoR) (9) and silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) (10), evidence suggests that VDR does not associate strongly with these corepressors (9 -12).Targeted gene deletion studies in mice (13, 14) and inactivat...

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Section: Resultsmentioning

confidence: 99%

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Hsieh

Sisk

Jurutka

et al. 2003

Journal of Biological Chemistry

207

201

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“…Carboplatin (mg/min/ml) [22][23][24][25] and other compounds 4,26 have been described. However, results from these therapies have generally been disappointing.…”

Section: Compound Median Total Auc (Lower-upper) Permanent Alopecia Imentioning

confidence: 99%

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

Jonge

Mathôt

Dalesio

et al. 2002

Bone Marrow Transplant

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Summary:Reversible alopecia is a commonly observed, important and distressing complication of chemotherapy. Permanent alopecia, however, is rare after standard-dose therapy, but has occasionally been observed after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC). We evaluated the relationships between total exposure to these three compounds and their different metabolites in the high-dose CTC regimen, and the subsequent development of irreversible alopecia. Twenty-four patients received two or three courses of high-dose CTC, each followed by peripheral blood progenitor cell transplantation. Plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its active metabolite tepa, and carboplatin were determined, and the area-under-theplasma concentration-versus-time curves (AUC) of the compounds were calculated. Eight of the 24 patients included in the study developed permanent alopecia, while seven had normal hair regrowth and nine patients developed incomplete and/or thin hair regrowth. The carboplatin AUC and the summed AUC of thiotepa and tepa were both significantly associated with increasing irreversibility of hair loss. These results suggest that high exposure to carboplatin and the sum of the thiotepa and tepa exposure may lead to the development of permanent alopecia. This knowledge could guide therapeutic drug monitoring in order to prevent the occurrence of permanent alopecia and thereby improve the patients' quality of life.

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“…A hair stimulating effect of such an antagonist has been observed in hairless mice and mice treated with cyclofosfamide [96][97][98]. So these topical PTH/PTH1R antagonists might be useful in chemotherapy induced alopecia [98]. Sporadic cases of PTH-related hair symptoms were reported in familial syndromes of hyper/hypoparathyroidism [99,100].…”

Section: Pthrp/pth1r Antogonists and Agonistsmentioning

confidence: 96%

“…Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth [96]. A hair stimulating effect of such an antagonist has been observed in hairless mice and mice treated with cyclofosfamide [96][97][98]. So these topical PTH/PTH1R antagonists might be useful in chemotherapy induced alopecia [98].…”

Section: Pthrp/pth1r Antogonists and Agonistsmentioning

confidence: 99%

Untitled

2017

EMIJ

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In this mini-review the role of parathyroid hormone-related peptide (PTHrP) in physiology and pathophysiology is discussed. Evolving from an unknown humoral factor in the HHM (Hypercalcemia of malignancy) syndrome its role as a "masterregulator" in the PTH family following identification is reviewed. PTHrP has more paracrine and autocrine functions in virtually all tissues than classical endocrine functions and is essential in embryonic, fetal and post-natal life. The physiological functions are near endless. The development of PTH/PTHrP receptor antagonist and agonists has been difficult and disappointing. Its role as a possible cytokine itself and as a regulatory thermogenesis factor in brown adipose tissue in cancer cachexia is discussed. PTHrP assays must be improved for PTHrP to be a reliable biomarker in oncology and to resolve the function of local proteolytic PTHrP fragments which are largely a mystery until now.

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A New Strategy for Modulating Chemotherapy-Induced Alopecia, Using PTH/PTHrP Receptor Agonist and Antagonist

Cited by 56 publications

References 31 publications

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Physical and Functional Interaction between the Vitamin D Receptor and Hairless Corepressor, Two Proteins Required for Hair Cycling

Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy

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