Temozolomide: An Updated Overview of Resistance Mechanisms, Nanotechnology Advances and Clinical Applications

Abstract

: Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6- guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with the tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.

Treatment of Human Glioblastoma U251 Cells with Sulforaphane and a Peptide Nucleic Acid (PNA) Targeting miR-15b-5p: Synergistic Effects on Induction of Apoptosis

“…At present, no curative treatment is available for GBM and the most used first-line drug, temozolomide (TMZ), is only able to cause an increase in the life expectancy of the treated patients, though this is still not satisfactory [4]. Therefore, new drugs are urgently needed for determining their possible employment in therapeutic protocols for anti-GBM treatments, also tackling important issues of the GBM management, such as the development of drug resistance [5][6][7][8][9][10].…”

“…Another very interesting possibility is that combined treatments might allow us to limit the issue of drug resistance, which is an impacting feature of several cancers [11,12,15]. In this respect, a high proportion of GBMs become TMZ-resistant with time [7][8][9][10].…”

Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin

“…Although TMZ is currently the only approved chemotherapeutic drug known to significantly improve the overall survival of GBM patients [ 47 , 48 ], the development of acquired TMZ resistance leading to treatment failure remains one of the challenges to be resolved. Numerous works aimed to understand intrinsic and acquired TMZ resistance and recent reviews dedicated to this topic are available [ 49 , 50 ]. It appears clear that a multifaceted view is to be considered related to the high molecular heterogeneity of GBM and the plasticity of GBM cells.…”

The Different Temozolomide Effects on Tumorigenesis Mechanisms of Pediatric Glioblastoma PBT24 and SF8628 Cell Tumor in CAM Model and on Cells In Vitro

“…4.9. Extraction of RNA from PBT24 and SF8628 Cell Line Cells PBT24 and SF8628 cell line cells were treated with 50 µMTMZ for 24 h. The concentration of 50 µM was chosen because it corresponds to the mean plasma concentration of the drug in TMZ-treated patients [65]. Control groups were cultured in a cell culture medium depending on the cell line.…”