Cytotoxicity of L-cycloserine against human neuroblastoma and medulloblastoma cells is associated with the suppression of ganglioside expression.
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.
Cinatl
J
J
Zentrum der Hygiene, Institut für Medizinische Virologie, Frankfurt am Main, Germany.
Cinatl
J
J
Kotchetkov
R
R
Pouckova
P
P
Vogel
J U
JU
Rabenau
H
H
Michaelis
M
M
Kornhuber
B
B
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
D005732:Gangliosides; D005678:G(M2) Ganglioside; C019403:ganglioside, GD2; D003523:Cycloserine