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CpG island hypermethylation of the DNA repair enzyme
methyltransferase predicts response to temozolomide in primary gliomas
Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L,
Garcia-Lopez JL, Piquer J, Safont MJ, Balana C, Sanchez-Cespedes M,
Garcia-Villanueva M, Arribas L, Esteller M
Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid,
Spain.
Purpose. The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT)
inhibits the killing of tumor cells by alkylating agents, and its loss in cancer
cells is associated with hypermethylation of the MGMT CpG island.
Thus,
methylation of MGMT has been correlated with the clinical response to
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas.
Here, we
investigate whether the presence of MGMT methylation in gliomas is also a good
predictor of response to another emergent alkylating agent, temozolomide.
Experimental Design. Using a methylation-specific PCR approach, we assessed the
methylation status of the CpG island of MGMT in 92 glioma patients who received
temozolomide as first-line chemotherapy or as treatment for relapses.
Results.
Methylation of the MGMT promoter positively correlated with the clinical
response in the glioma patients receiving temozolomide as first-line
chemotherapy (n = 40).
Eight of 12 patients with MGMT-methylated tumors (66.7%)
had a partial or complete response, compared with 7 of 28 patients with
unmethylated tumors (25.0%; P = 0.030).
We also found a positive association
between MGMT methylation and clinical response in those patients receiving BCNU
(n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea
(n = 17, P = 0.043) as first-line chemotherapy.
Overall, if we analyze the
clinical response of all of the first-line chemotherapy treatments with
temozolomide, BCNU, and
procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation
to the MGMT methylation status, MGMT hypermethylation was strongly associated
with the presence of partial or complete clinical response (P < 0.001).
Finally, the MGMT methylation status determined in the initial glioma tumor did
not correlate with the clinical response to temozolomide when this drug was
administered as treatment for relapses (P = 0.729).
Conclusions. MGMT
methylation predicts the clinical response of primary gliomas to first-line
chemotherapy with the alkylating agent temozolomide.
These results may open up
possibilities for more customized treatments of human brain tumors.
PMID: 15297393 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15297393
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