, Volume 82, Issue 1, pp 85-89
Date: 20 Sep 2006

Local intracerebral administration of O6-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma

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The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O6-benzylguanine (O6BG), sensitizes tumor cells to O6-alkylating agents. However, systemic administration of O6BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O6-alkylating drugs administered together with O6BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O6BG of a patient suffering from glioblastoma. O6BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O6BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O6BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O6-alkylating drugs) concomitant with O6BG without augmenting drug-induced systemic side effects.