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.


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.


CONCLUSIONS
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.
Najim
N
N
Kidscan Children's Cancer Research Centre, Biomedical Sciences Research Institute, School of Environment and Life Sciences, University of Salford, Salford M54WT, UK.
Podmore
I D
ID
McGown
A
A
Estlin
E J
EJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002945:Cisplatin / Q000008:administration & dosage; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005470:Fluorometry; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008715:Methionine / Q000172:deficiency*; D008727:Methotrexate / Q000008:administration & dosage; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D008715:Methionine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D005978:Glutathione; D002945:Cisplatin; D000077204:Temozolomide; D008727:Methotrexate