title: Cytotoxicity of L-cycloserine against human neuroblastoma and medulloblastoma cells is associated with the suppression of ganglioside expression.
abstract: BACKGROUND
  Human neuroblastoma and medulloblastoma express abnormal ganglioside patterns especially GD2 and GM2 which are important for tumour growth. We tested the effects of L-cycloserine (L-CS), a potent inhibitor of synthesis of glycosphingolipids, on the growth, viability and expression of GD2 and GM2 in neuroblastoma and medulloblastoma cells.
  
  
  METHODS
  The cytotoxic effects of L-CS were tested using the MTT dye reduction assay on four neuroblastoma (IMR-32, SK-N-SH, UKF-NB-2 and UKF-NB-3), two medulloblastoma (D283 and D341) and normal human fibroblasts and epithelial cell lines. In some experiments cytotoxicity of L-CS was tested in the presence of exogenous GD2 and GM2. The expression of GD2 and GM2 was analysed by flow cytometry. The antitumoral effects of L-CS in vivo were assessed on established xenografts of UKF-NB-3 or D283 cells in athymic (nude) mice using systemic administration of the drug (150 mg/kg intraperitoneally, once per day on 20 consecutive days).
  
  
  RESULTS
  In vitro experiments revealed that L-CS was toxic for tumour cells at concentrations ranging from 0.5 to 20 micrograms/ml without any significant effects on normal fibroblasts and epithelial cells. L-CS treatment of UKF-NB-3 and D283 cells significantly inhibited expression of GD2 and GM2. The addition of exogenous GD2 and GM2 to culture medium partially prevented cytotoxic effects of L-CS on tumour cells. In vivo treatment resulted in complete tumour regression of UKF-NB-3 xenografts whereas growth of D283 xenografts was reduced by 60%.
  
  
  CONCLUSIONS
  L-CS is a selective antitumoral agent for neuroblastoma and medulloblastoma cells with the ability to reduce expression of tumour associated gangliosides. In vivo experiments suggest that L-CS may be effective drug for treatment of neuroblastoma and medulloblastoma.
authors.affiliation: Zentrum der Hygiene, Institut für Medizinische Virologie, Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
authors.forename: R
authors.initials: R
authors.lastname: Kotchetkov
authors.forename: P
authors.initials: P
authors.lastname: Pouckova
authors.forename: J U
authors.initials: JU
authors.lastname: Vogel
authors.forename: H
authors.initials: H
authors.lastname: Rabenau
authors.forename: M
authors.initials: M
authors.lastname: Michaelis
authors.forename: B
authors.initials: B
authors.lastname: Kornhuber
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003523:Cycloserine / Q000494:pharmacology*; D005678:G(M2) Ganglioside / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D005732:Gangliosides; D005678:G(M2) Ganglioside; C019403:ganglioside, GD2; D003523:Cycloserine