title: Combined Hydroxyurea and Verapamil in the Clinical Treatment of Refractory Meningioma: Human and Orthotopic Xenograft Studies.
abstract: OBJECTIVE
  Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model.
  
  
  METHODS
  Six women and 1 man, aged 26-76 years (median, 56 years), with magnetic resonance imaging-proven progression of ≥ 25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120-240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability.
  
  
  RESULTS
  After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 ± 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges.
  
  
  CONCLUSIONS
  Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation.
authors.affiliation: Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karsy
authors.affiliation: School of Medicine, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Hoang
authors.affiliation: School of Medicine, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Talmadge
authors.initials: T
authors.lastname: Barth
authors.affiliation: Department of Radiation Oncology, University of Utah, Salt Lake City, Utah, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Burt
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dunson
authors.affiliation: Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Gillespie
authors.affiliation: Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA; Department of Radiation Oncology, University of Utah, Salt Lake City, Utah, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA. Electronic address: randy.jensen@hsc.utah.edu.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D003692:Delayed-Action Preparations; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D008297:Male; D008579:Meningioma / Q000188:drug therapy*; D051379:Mice; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D016896:Treatment Outcome; D014700:Verapamil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D014700:Verapamil; D006918:Hydroxyurea
keywords: Calcium channel antagonists; Hydroxyurea; Meningioma; Verapamil