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Correlation
of tumor O6 methylguanine-DNA methyltransferase levels with survival of
malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a
Southwest Oncology Group study
Jaeckle KA, Eyre HJ, Townsend JJ, Schulman S, Knudson HM, Belanich M,
Yarosh DB, Bearman SI, Giroux DJ, Schold SC
The University of Texas M.D. Anderson Cancer Center,
Houston, USA
Purpose. Prior studies show that increased levels of the DNA repair
protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as
O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of
glioma cell lines to nitrosoureas.
The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision
repair negative [MER-]) and those repair-proficient lines pretreated with
MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that
tumor MGMT levels may be an important predictor of survival in patients with
gliomas.
Patients and Methods. We correlated the MGMT level in malignant
astrocytoma tissues, obtained from patients treated with radiotherapy and
bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest
Oncology Group [SWOG] 8737), with overall and failure-free survival.
Results. Of 64 assessable patients with malignant astrocytoma (63%
glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000
molecules/nucleus) MGMT levels.
The overall median survival for patients with high versus low MGMT levels was 8
and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6
months, respectively (P=.008).
Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma
was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months
(n=40).
The overall hazards ratio (risk for death) for high versus low MGMT levels was
3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19;
age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60
years (1.11).
Multivariate analysis showed that MGMT was independent of other known prognostic
factors (age, performance status, histology).
Conclusion. The MGMT level in tumor tissue specimens may be a predictive
marker of survival in patients with malignant astrocytoma that is independent of
other previously described prognostic variables.
PMID: 9779706 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9779706&dopt=Abstract
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