Methionine restriction reduces the chemosensitivity of central nervous system tumour cell lines.

BACKGROUND The aim of this study was to investigate the effects of methionine depletion with cytotoxic agents that are potentially influenced by depletion of methionine, and are known to have a role in CNS tumour treatments for children. MATERIALS AND METHODS Cytotoxicity studies and synergistic interactions were assayed by SRB assay. Glutathione levels were assayed by HPLC after derivatization with OPA. MGMT activity was determined by a restriction endonuclease inhibition assay. RESULTS Methionine depletion causes a demonstrable increase in glutathione levels for medulloblastoma (Daoy) and glioma (D54) cells, with a decrease in MGMT activity for Daoy cells. For both cell lines, methionine depletion reduces their sensitivity to a range of chemotherapy agents that interface at the level of methionine metabolism, namely temozolomide, cisplatin and methotrexate. CONCLUSION The results show that methionine depletion increases the resistance of tumour cells to the chemotherapeutic agents tested. However, in methionine-replete conditions, we have demonstrated synergistic activity for various combinations of chemotherapeutic agents that are hitherto unreported and may have clinical utility for the treatment of children with CNS tumours.