Calcipotriol Inhibits Autocrine Phosphorylation of EGF Receptor in a Calcium-Dependent Manner, a Possible Mechanism for Its Inhibition of Cell Proliferation and Stimulation of Cell Differentiation

Lee, EunAh; Jeon, Sang-Hak; Yi, Jianxun; Jin, Yong Jae; Son, Young-Jun

doi:10.1006/bbrc.2001.4943

Cited by 22 publications

(16 citation statements)

References 26 publications

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“…The first dose level of calcitriol was 10 Ag. Subsequent dose escalation levels were 15,20,26,34,44,57,74, and 96 Ag/wk. No intrapatient escalation was allowed.…”

Section: Methodsmentioning

confidence: 99%

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A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Fakih

Trump

Muindi

et al. 2007

Clinical Cancer Research

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Purpose: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. Experimental Design: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. Results: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 Ag/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 Ag/wk calcitriol dose level.The relationship between calcitriol dose and peak serum calcitriol (C max ) and systemic exposure (AUC) was linear. Mean (FSD) serum calcitriol C max at the MTD was 6.68 F 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. Conclusions: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 Ag calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.

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“…The first dose level of calcitriol was 10 Ag. Subsequent dose escalation levels were 15,20,26,34,44,57,74, and 96 Ag/wk. No intrapatient escalation was allowed.…”

Section: Methodsmentioning

confidence: 99%

“…Skin biopsies were scheduled around 8 h from calcitriol and/or gefitinib dosing. Biopsy timing was selected based on preclinical data supporting maximum EGFR phosphorylation inhibition after 8 h from treatment with a calcitriol analogue (15).…”

mentioning

confidence: 99%

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Fakih

Trump

Muindi

et al. 2007

Clinical Cancer Research

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“…In addition, the synthetic vitamin D 3 analogue, calcipotriol (also known as MC-903), is also very potent in the topical treatment of psoriasis (7,8). Calcipotriol is much less potent in calcium metabolism than vitamin D 3 , but retains similar effects on cell proliferation and differentiation in human lymphoma cell line U937, human keratinocyte, and squamous carcinoma cell line SCC13 in the 3-D raft culture (9)(10)(11). The inhibition of keratinocyte proliferation and the induction of differentiation are consistent with its anti-psoriatic activity.…”

Section: Introductionmentioning

confidence: 64%

“…Experiments also revealed that calcipotriol reduces interleukin-19 (IL-19) and -20 (IL-20) after calcipotriol treatment (16). To our knowledge, the only attempt to elucidate the mechanism of how calcipotriol decreases proliferation of the keratinocytes was done by Lee et al (11), who reported that calcipotriol inhibits autocrine phosphorylation of the EGF receptor causing its deactivation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the identity of the latter has not been established nor was any of the involved genes unequivocally linked to the proliferation. Recently, it was only proposed that calcipotriol might decrease cell proliferation by deactivating EGF receptor (11). Therefore, identification of genes modulated by calcipotriol would help to clarify the mechanism of action of the drug, and would reveal potential targets for more specific treatment of psoriasis.…”

Section: Introductionmentioning

confidence: 99%

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Calcipotriol Affects Keratinocyte Proliferation by Decreasing Expression of Early Growth Response-1 and Polo-like Kinase-2

et al. 2007

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Topical Calcipotriol for Preventive Treatment of Hypertrophic Scars

Veer¹,

Jacobs²,

Waardenburg³

et al. 2009

Arch Dermatol

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To evaluate the efficacy of topical application of calcipotriol to healing wounds in preventing or reducing hypertrophic scar formation and to investigate the biochemical properties of the epidermis associated with hypertrophic scar formation. Design: Randomized, double-blind, placebo-controlled trial using the reduction mammoplasty wound-healing model. Setting: University Medical Center Groningen. Patients: Thirty women who underwent bilateral reduction mammoplasty. Interventions: For 3 months, scar segments were treated with either topical calcipotriol or placebo. Main Outcome Measures: Three weeks, 3 months, and 12 months postoperatively, the scars were evaluated and punch biopsy samples were collected for immunohistochemical analysis. Results: No significant difference in the prevalence of hypertrophic scars was observed between the placeboand calcipotriol-treated scars. Only scars with activated keratinocytes 3 weeks postoperatively became hypertrophic (P=.001). Conclusions: Topical application of calcipotriol during the first 3 months of wound healing does not affect the incidence of hypertrophic scar formation. We observed a strong association between keratinocyte activation and hypertrophic scar formation.

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Calcipotriol Inhibits Autocrine Phosphorylation of EGF Receptor in a Calcium-Dependent Manner, a Possible Mechanism for Its Inhibition of Cell Proliferation and Stimulation of Cell Differentiation

Cited by 22 publications

References 26 publications

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Calcipotriol Affects Keratinocyte Proliferation by Decreasing Expression of Early Growth Response-1 and Polo-like Kinase-2

Topical Calcipotriol for Preventive Treatment of Hypertrophic Scars

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