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

• Julia E. Stokes

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

• Michael S. Bobola

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

• Marc C. Chamberlain

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

• John R. Silber

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

 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.

Chamberlain MC. Evolving strategies: Future treatment of glioblastoma. Expert Rev of Neurotherapeutics 2011; 11(4): 519-32. http://dx.doi.org/10.1586/ern.11.30

Armstrong TS, Cao Y, Scheurer ME, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol 2009; 11: 825-32. http://dx.doi.org/10.1215/15228517-2008-120

Villano JL, Letarte N, Yu JM, Abdur S, Bressler LR. Hematologic adverse events associated with temozolomide. Cancer Chemother Pharmacol 2012; 69(1): 107-113. 2011 May 26.

Christmann M, Verbeek B, Roos WP, Kaina B. O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry. Biochim Biophys Acta 2011; 1816: 179-90.

Jansen M, Bardenheuer W, Sorg UR, Seeber S, Flasshove M, Moritz T. Protection of hematopoietic cells from O6-alkylation damage by O6-methylguanine DNA methyltransferase gene transfer: studies with different O6-alkylating agents and retroviral backbones. Eur J Haematol 2001; 67: 2-13. http://dx.doi.org/10.1034/j.1600-0609.2001.067001002.x

Sabharwal A, Waters R, Danson S, et al. Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells. Melanoma Res 2011; 21: 502-508. http://dx.doi.org/10.1097/CMR.0b013e32832ccd58

Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS. O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 1999; 5: 807-14.

Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2009; 343: 1350-54. http://dx.doi.org/10.1056/NEJM200011093431901

Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352: 997-1003. http://dx.doi.org/10.1056/NEJMoa043331

Sylvester RK, Steen P, Tate JM, et al. Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients. Anticancer Drugs 2011; 22: 104-10. http://dx.doi.org/10.1097/CAD.0b013e3283407e9f

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