A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

Abstract

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.

Keywords: combination therapeutics; glioblastoma; treatment resistance.

Figure 1

The TMZ mechanisms of action and intranuclear pathways for DNA repair leading to resistance and potential therapeutic approaches to overcome resistance to TMZ. At the physiological pH, TMZ is hydrolyzed to its active metabolite, 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide(MTIC), which is subsequently converted to the pharmacologically active methyl diazonium and the inactive 5-aminoimidazole-4-carboxamide (AIC). The alkylating entity methyl diazonium participates in the methylation of O⁶ and N⁷ positions of the guanine and N³ position of adenine residues in DNA, respectively, leading to DNA double strand breaks (DSBs), which, in turn, activate apoptotic pathways in tumor cells [12,13]. Structures: 2D Structures were obtained from Pubchem (CID listed below): TMZ: 5394; MTIC: 76953; AIC: 9679; Methyl diazonium: 115287; O⁶-meG: 656275; N⁷-meG:135398679; N³-meA: 135398661.