PRS AAPS Oral Proofs 2016
James E. McCarthy, MD, Timothy W. King, MD, PhD
From the University of Wisconsin-Madison, Madison, Wis.
PURPOSE: Infantile hemangiomas demonstrate involution after oral and topical β blockers. We sought to determine (1) administration route on tumor involution, (2) β receptor selectivity on gene expression, and (3) effect of mesenchymal cell type on gene expression.
METHODS: Human infantile hemangioma endothelial stem cells (HemESCs) and endothelial cells were grown to 90% confluence, and media was exchanged to 50 μg/μl and 100 μg/μl concentrations of metoprolol (β-1 blocker) and propranolol (nonselective β blocker), respectively, for 72 hours. Reverse transcription polymerase chain reaction was used to assess gene expression of HIF-a, VEGF-a, VEGF-a1 receptor, VEGF-a2 receptor, and PDGF-β. The dorsum of 8-week-old nude athymic mice were injected with 200 μl of HemESCs and human infantile hemangioma endothelial cells in matrigel at 1 × 106 cells/μl per cell line. Six mice per β blocker per route were treated with 0.2 mg/kg oral, local injection of 0.2 mg/kg, or 1% topical preparations twice daily for 2 weeks during when tumors were explanted. Differences in tumor volume and microvascular density were analyzed.
RESULTS: HemESCs exposed to propranolol had a 1.5-fold reduction in expression of HIF-a and VEGF-a in a dose-dependent manner (P = 0.05). There were no differences in tumor volume between administration routes; however, oral administration trended toward greater reduction in microvascular density (P = 0.08).
CONCLUSIONS: Nonselective β blockade leads to greater inhibition of HIF-a and VEGF-a compared with selective β blockade, particularly in HemESCs. Oral administration of β blockers appears to produce greater reduction in microvascular density.