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Low Leukocyte MGMT Accompanies Temozolomide-Induced Myelotoxicity in Brain Tumor Patients - Pages 44-48

Julia E. Stokes, Michael S. Bobola, Marc C. Chamberlain and John R. Silber

Departments of Neurological Surgery (JES, MSB, MCC, JRS), and Neurology (MCC), University of Washington, USA





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    Abstract: Objective: The methylating agent temozolomide (TMZ) has markedly improved clinical outcome for patients with glioblastoma and other gliomas. While TMZ has comparatively low systemic toxicity, a minority of patients experience severe myelotoxicity that compromises TMZ treatment, necessitating dose reductions and treatment delays. These limitations emphasize the need to develop markers to identify individuals susceptible to TMZ-induced myelosuppression. The purpose of this small pilot study is to examine the association between treatment-limiting myelosuppression in primary brain tumor patients receiving TMZ and expression of O6-methylguanine-DNA methyltransferase (MGMT) in peripheral blood leukocytes (PBL). MGMT is the sole human activity that removes TMZ-induced, cytotoxic O6-methylguanine adducts from DNA.

    Methods: MGMT biochemical activity and MGMT promoter methylation status, a surrogate measure of MGMT expression, were assayed in PBL from 10 patients who experienced treatment-limiting myelotoxicity during TMZ therapy, 8 patients who experienced no myelotoxicity during TMZ treatment, and 10 disease-free, untreated controls.

    Results: MGMT activity was detectable in all 28 PBL samples, and all displayed an unmethylated promoter indicative of MGMT expression. Mean PBL MGMT activity was 2-fold lower in patients who experienced myelotoxicity compared to patients without myelotoxicity (8.9 ± 3.9 vs. 18 ± 8.1 fmol/106 cells; P ≤ 0.015) and to untreated controls (8.9 ± 3.9 vs. 16 ± 6.8 fmol/106 cells; P ≤ 0.015).

    Conclusions: These preliminary data indicate that low MGMT activity in PBL is associated with myelotoxicity in primary brain tumor patients receiving TMZ, and may have value if confirmed in a larger study as a marker to identify patients at greater risk of treatment-limiting myelosuppression.

    Keywords: Primary brain tumor, temozolomide (TMZ), glioblastoma, myelosuppression, thrombocytopenia, O6-methylguanine-DNA methyltransferase, promoter methylation, MGMT enzymatic activity, peripheral blood leukocytes, biomarkers


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