New (alternative) temozolomide regimens for the treatment of glioma

Abstract

One barrier to successful treatment of malignant glioma is resistance to alkylating agents such as temozolomide. The cytotoxic activity of temozolomide and other alkylating agents is believed to manifest largely by the formation of O(6)-methylguanine DNA adducts. Consequently, the primary mechanism of resistance to temozolomide is a function of the activity of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT). Fortuitously, MGMT is inactivated after each reaction (i.e., suicide enzyme). Therefore, if the rate of DNA alkylation were to outpace the rate of MGMT protein synthesis, the enzyme could, in theory, be depleted. Several studies have shown that prolonged exposure to temozolomide can deplete MGMT activity in blood cells, a process that could potentially increase the antitumor activity of the drug. To date, however, there are limited data demonstrating the depletion of MGMT activity in tumor tissue exposed to temozolomide. A variety of dosing schedules that increase the duration of exposure and the cumulative dose of temozolomide are currently being investigated for the treatment of glioma, with the goal of improving antitumor activity and overcoming resistance. These alternative dosing regimens have been shown to deplete MGMT activity in peripheral blood mononuclear cells, but the regimen that provides the best balance between enhanced antitumor activity and acceptable hematologic toxicity has yet to be determined.

Temozolomide induces autophagy in primary and established glioblastoma cells in an EGFR independent manner

“…2). This indicates that the cellular supply of MGMT is exhausted when repairing methylated TMZ lesions, concordant with the findings of Wick et al (29). The primary cell lines pGBM T1 and pGBM T12 did not express MGMT, which may be interpreted as favorable regarding TMZ treatment.…”

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

“…Although irradiation plus concomitant and adjuvant chemotherapy with temozolomide represents the standard of care for patients with glioblastoma (32), resistance to these therapies is encountered during primary therapy, particularly in elderly patients (33), or in the recurrent setting despite considerable efforts to intensify chemotherapeutic regimens with the aim at overcoming primary or secondary resistance (34). Although the activities of methyltransferases, particularly MGMT, have evolved as major factors predicting response to alkylating agents in the primary setting (35), the factors, which are induced by primary therapeutic measures and constitute resistance in the recurrent setting beyond functional alterations in DNA mismatch repair capabilities (36), are incompletely understood.…”

Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases

“…Alternative regimens of temozolomide treatment, such as 3 weeks on and 1 week off, have also been explored to overcome chemoresistance of brain tumors (25,26). Bush et al (23) chose the 3 weeks on and 1 week off protocol to treat seven patients with aggressive pituitary tumors (including two carcinomas) because the high dose of temozolomide per unit time might theoretically deplete tumor cells of their MGMT more efficiently than the standard regimen.…”