Journal of Clinical Oncology, Vol 16, 3310-3315, Copyright © 1998 by American Society of Clinical Oncology
Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis- chloroethylnitrosourea: a Southwest Oncology Group study
KA Jaeckle, HJ Eyre, JJ Townsend, S Schulman, HM Knudson, M Belanich, DB Yarosh, SI Bearman, DJ Giroux and SC Schold
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.
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C. L. Nutt, N. A. Loktionova, A. E. Pegg, A. F. Chambers, and J.g. Cairncross
O6-Methylguanine-DNA methyltransferase activity, p53 gene status and BCNU resistance in mouse astrocytes
Carcinogenesis,
December 1, 1999;
20(12):
2361 - 2365.
[Abstract]
[Full Text]
[PDF]
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Z.-P. Chen, J. Remack, T. P. Brent, G. Mohr, and L. C. Panasci
Extraneuronal Monoamine Transporter Expression and DNA Repair Vis-a-Vis 2-Chloroethyl-3-sarcosinamide-1-nitrosourea Cytotoxicity in Human Tumor Cell Lines
Clin. Cancer Res.,
December 1, 1999;
5(12):
4186 - 4190.
[Abstract]
[Full Text]
[PDF]
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D. M. Kokkinakis, R. C. Moschel, A. E. Pegg, and S. C. Schold
Eradication of Human Medulloblastoma Tumor Xenografts with a Combination of O6-Benzyl-2'-deoxyguanosine and 1,3-Bis(2-chloroethyl)-1-nitrosourea
Clin. Cancer Res.,
November 1, 1999;
5(11):
3676 - 3681.
[Abstract]
[Full Text]
[PDF]
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M. Eileen Dolan, B. L. McRae, E. Ferries-Rowe, M. Belanich, G. A. van Seventer, J. Guitart, D. Pezen, T. M. Kuzel, and D. B. Yarosh
O6-Alkylguanine-DNA Alkyltransferase in Cutaneous T-Cell Lymphoma: Implications for Treatment with Alkylating Agents
Clin. Cancer Res.,
August 1, 1999;
5(8):
2059 - 2064.
[Abstract]
[Full Text]
[PDF]
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