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O(6)-methyl-guanine-DNA
methyltransferase Methylation in Serum and Tumor DNA Predicts Response to
1,3-Bis(2-Chloroethyl)-1-Nitrosourea but not to Temozolamide Plus Cisplatin in
Glioblastoma Multiforme
Balana C,
Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P,
Sanchez JJ, Rosell R
Medical
Oncology Service [C. B., J. L. R., M. T., C. S., P. M., R. R.], Neurosurgery [Y.
R.], Pathology [A. A.], and Radiotherapy [C. B.], Hospital Germans Trias i Pujol,
08916 Badalona (Barcelona), and Free University of Madrid, Madrid [J. J. S.],
Spain.
Purpose.
In glioblastoma multiforme (GBM), the cytotoxic effect of
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolamide is dependent on
O(6) alkylation, which correlates inversely with expression of the DNA repair
enzyme O(6)-methyl-guanine-DNA methyltransferase (MGMT).
Thus, MGMT assessment can be useful in predicting response in GBM, but the
scarcity of neoplastic cells limits the practicality of MGMT assessment in these
tumors.
Although GBM grows within the skull, we investigated the concordance of
methylation in glioma tissue, and paired serum DNA and the potential correlation
with response and time to progression.
Experimental
Design. Using MSP assay, we assessed the methylation of MGMT, p16, DAPK, and
RASSF1A in tumor and serum DNA from 28 GBM patients treated with BCNU or with
temozolamide plus cisplatin.
Results.
The concordance between methylation in tumor and serum was highly significant.
Overall, response plus stable disease was noted in 10 of 11 (90.9%) patients
with MGMT methylation and in 5 of 14 (35.7%) patients without (P = 0.01).
In the 16 patients treated with temozolamide plus cisplatin, no significant
correlation between MGMT methylation status and response was observed, whereas
in BCNU-treated patients, a significant difference was observed in favor of
those with methylated MGMT.
Time to progression was 29.9 weeks in 12 patients with MGMT methylation and 15.7
weeks in 10 patients without (P = 0.006).
No correlation was observed between response or time to progression and p16,
DAPK, or RASSF1A methylation.
Conclusions.
Methylated MGMT, p16, DAPK, and RASSF1A were found in serum DNA of GBM patients,
with a good correlation between serum and primary tumor tissue.
Serum MGMT methylation predicted response and time to progression in BCNU-treated
GBM patients.
The methylation-specific PCR assay in serum DNA could be a good predictive tool
for selecting GBM patients to be treated with BCNU or alternatively with the
combination of temozolamide plus cisplatin.
PMID:
12684420 [PubMed - in process]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12684420&dopt=Abstract
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