Delayed repletion of O6-methylguanine-DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity.
J Neurosurg
; 98(3): 591-8, 2003 Mar.
Article
em En
| MEDLINE
| ID: mdl-12650433
ABSTRACT
OBJECT Temozolomide (TMZ)-induced O6-methylguanine (MG) DNA lesions, if not removed by MG-DNA methyltransferase (MGMT), mispair with thymine, trigger rounds of futile mismatch repair (MMR), and in glioma cells lead to prolonged G2-M arrest and ultimately cell death. Depletion of MGMT by O6-benzylguanine (BG) sensitizes tumor cells to TMZ, and this combination is currently used in clinical trials. The use of the TMZ+BG combination in gliomas, however, is complicated by the prolonged TMZ-induced G2-M arrest, which may delay activation of poorly defined cell death pathways and allow for MGMT repletion and reversal of toxicity. METHODS:
To address these issues, the actions of TMZ were monitored in DNA MMR-proficient SF767 glioma cells depleted of MGMT by BG, and in cells in which BG was removed at various times after TMZ exposure. In MGMT-depleted cells, TMZ exposure led to DNA single-strand breaks and phosphorylation of cdc2, followed by G2-M arrest, induction of p53/p21, and DNA double-strand breaks. Although DNA single-strand breaks, phosphorylation of cdc2, and G2-M arrest could be reversed by repletion of MGMT up to 5 days after TMZ exposure, TMZ-induced cytotoxicity could only be prevented if MGMT was replenished within 24 hours of the onset of G2-M arrest, and before the creation of DNA double-strand breaks.CONCLUSIONS:
These results indicate that although SF767 glioma cells undergo a prolonged G2-M arrest in response to TMZ, their ability to escape TMZ-induced cytotoxicity by MGMT repletion is limited to an approximately 24-hour period after the onset of G2-M arrest.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antineoplásicos Alquilantes
/
O(6)-Metilguanina-DNA Metiltransferase
/
Dacarbazina
/
Glioma
/
Guanina
Limite:
Humans
Idioma:
En
Revista:
J Neurosurg
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Estados Unidos