Levetiracetam as a Temozolomide-Sensitizer for Glioblastoma
Levetiracetam as a Temozolomide-Sensitizer for Glioblastoma
Abstract & Commentary
By Adília Hormigo, MD, PhD, Attending Neurologist, Memorial Sloan-Kettering Cancer Center, and Assistant Professor of Neurology, Weill Medical College of Cornell University. Dr. Hormigo reports no financial relationships relevant to this field of study.
Synopsis: In addition to its efficacy as an antiepileptic, and its lack of P-450 enzyme induction, levetiracetam also may enhance the chemotherapeutic effects of temozolomide in the treatment of glioblastoma.
Source: Bobustuc GC, et. al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-Oncology 2010;12:917-927.
Patients with glioblastoma multiforme (GBM) frequently have seizures that occur either at presentation or during the course of their disease. These seizures often are difficult to control. Levetiracetam is one of the anti-epileptic drugs (AEDs) currently used for seizure prophylaxis in patients with GBM. The conventional treatment of a GBM is surgical resection followed by radiotherapy with concurrent chemotherapy using temozolomide, followed by adjuvant temozolomide. The identification of the promoter of methylation of O6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene in some GBM patients confers a favorable treatment response to temozolomide and longer patient survival.
In this paper, the authors reported on their in vitro studies showing that concentrations of levetiracetam in the therapeutic range decreases MGMT by enhancing binding of p53 to MGMT promoter and by recruiting a histone deacetylase corepressor complex (HDAC1). They confirm their observation of levetiracetam effect on MGMT by examining the tissue samples in four patients before and after levetiracetam treatment and showed inhibition of MGMT expression after treatment with this AED.
Commentary
Levetiracetam often has been used as the first-line AED in patients with GBM because it does not induce cytochrome P450 and has no interaction with most chemotherapy agents. In a disease with such a dismal prognosis, it is important to use AEDs that do not diminish the effect of chemotherapy agents. Furthermore, most clinical trials have as an exclusion criteria the use of enzyme- inducing AEDs for seizure prophylaxis, such as carbamazepine, oxcarbazepine, phenytoin, and phenobarbital, which all induce CYP3A4, a member of the cytochrome P450 family of enzymes, as opposed to non-enzyme- inducing AEDs. The use of AEDs that are considered non-enzyme-inducing, such as levetiracetam, valproic acid, lamotrigine, gabapentin, zonisamide, topiramate, and lacosamide, usually is allowed for enrollment in clinical trials for treatment of patients with GBM.
In this paper, the authors suggest that levatiracetam, one of the non-enzyme-inducing AEDs, promotes another mechanism for the epigenetic silencing of MGMT. This may be relevant for treatment of GBM, including those tumors where MGMT is unmethylated. The authors acknowledge the limitations of their observation and the need to expand their study to a larger number of cell lines and to correlate with MGMT levels. This is only one factor among many that may affect the response to temozolomide treatment and ultimately affect the response of the patient to treatment.
Reference
1. Hegi ME, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Eng J Med 2005;352:997-1003.
In addition to its efficacy as an antiepileptic, and its lack of P-450 enzyme induction, levetiracetam also may enhance the chemotherapeutic effects of temozolomide in the treatment of glioblastoma.Subscribe Now for Access
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