Journal
CURRENT NEUROPHARMACOLOGY
Volume 19, Issue 4, Pages 513-537Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1570159X18666200626204005
Keywords
Alkylating agents; drug resistance; chemotherapy; nanoparticles; cancer; clinical trials
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Funding
- Junta de Andalucia (PAIDI group CTS107)
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Temozolomide is an oral alkylating prodrug commonly used in the treatment of high-grade gliomas, with high oral bioavailability and the ability to cross the blood-brain barrier. However, despite its efficacy, patient survival remains relatively short, largely due to tumor drug resistance. Understanding the mechanisms of resistance is crucial for the development of new therapeutic strategies to improve clinical outcomes.
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 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.
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