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

Abstract

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O(6)-benzylguanine (O(6)BG), sensitizes tumor cells to O(6)-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O(6)-alkylating drugs administered together with O(6)BG 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 O(6)BG of a patient suffering from glioblastoma. O(6)BG 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 O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O(6)-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6- methylguanine-DNA methyltransferase (MGMT).

“…A combination of Bg with alkylating agents, improved the efficacy of glioma treatment and other solid tumors considering its toxic limitations. 30,31 hMutSalpha is probably the main 6-TG repair enzyme through recognition of 6-methylthioguanine. 32 MGMT is probably not the main repair enzyme for 6-TG damage but based on our evidence it has an important role.…”

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

“…72 The feasibility of administering O 6 -BG locally into the tumor cavity via an Ommaya reservoir, in combination with systemic temozolomide, has been explored in a single patient. 73 With the aim of increasing the dose-limiting tolerance of the bone marrow towards …”

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

“…To overcome MGMT-related chemotherapy resistance in gliomas, a wide range of therapeutic strategies are currently under trial such as intensified and continuous TMZ regiments [47][48][49] and treatment with MGMT inhibitors. 8,50,51 It is conceivable that knowledge on MGMT level of a given tumor will be guiding therapy as to dose and time course of administration of O 6 -alkylating drugs as well as MGMT inhibitors.…”