title: Trabectedin has promising antineoplastic activity in high-grade meningioma.
abstract: BACKGROUND
  Meningiomas are common intracranial tumors arising from the meninges and usually are benign. However, a few meningiomas have aggressive behavior and, for such patients, effective treatment options are needed. Trabectedin is a novel, marine-derived, antineoplastic agent that has been approved and is used routinely as therapy for advanced soft tissue sarcoma and ovarian cancer.
  
  
  METHODS
  The authors investigated the in vitro effects of trabectedin alone and in combination with hydroxyurea, cisplatin, and doxorubicin in primary cell cultures of benign (n = 9), atypical (n = 6), and anaplastic (n = 4) meningiomas using chemosensitivity assays (3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT]), Western blot analysis, cell cycle analysis, and immunofluorescent staining.
  
  
  RESULTS
  Strong antimeningioma activity of trabectedin was observed and was characterized by distinct cell cycle arrest, down-regulation of multiple cyclins, deregulated expression of cell death-regulatory genes, and massive apoptosis induction. Cytotoxic activity was especially intense in higher grade meningiomas with a half-maximal inhibitory concentration <10 nM. Combination with trabectedin synergistically enhanced the antimeningioma activity of hydroxyurea but also enhanced the activity of doxorubicin and cisplatin. On the basis of these findings, trabectedin was given to 1 patient who had heavily pretreated, anaplastic meningioma, and a favorable response was observed with radiologic disease stabilization, marked reductions in brain edema and requirement for corticosteroids, and improvement of clinical symptoms. However, treatment had to be discontinued after 5 cycles because of adverse drug effects.
  
  
  CONCLUSIONS
  The current results indicated that trabectedin may represent a promising new therapeutic option for patients with aggressive meningioma and should be evaluated in prospective clinical studies.
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.forename: Sabine
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: Daniela
authors.initials: D
authors.lastname: Lötsch
authors.forename: Adelheid
authors.initials: A
authors.lastname: Wöhrer
authors.forename: Maria
authors.initials: M
authors.lastname: Schmook
authors.forename: Karin
authors.initials: K
authors.lastname: Dieckmann
authors.forename: Walter
authors.initials: W
authors.lastname: Saringer
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D004149:Dioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000077606:Trabectedin; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin