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Review
. 2021 May 17;10(5):1225.
doi: 10.3390/cells10051225.

From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Xueyuan Sun  1 , Sevin Turcan  1
Affiliations
Review

From Laboratory Studies to Clinical Trials: Temozolomide Use in IDH-Mutant Gliomas

Xueyuan Sun et al. Cells. .

Abstract

In this review, we discuss the use of the alkylating agent temozolomide (TMZ) in the treatment of IDH-mutant gliomas. We describe the challenges associated with TMZ in clinical (drug resistance and tumor recurrence) and preclinical settings (variabilities associated with in vitro models) in treating IDH-mutant glioma. Lastly, we summarize the emerging therapeutic targets that can potentially be used in combination with TMZ.

Keywords: IDH-mutant glioma; TMZ; combination therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Epigenetic alterations induced by IDH mutations and potential drug targets for TMZ combination therapy. (a) Cellular epigenetic regulation without IDH mutation; (b) cellular epigenetic alterations in IDH-mutant gliomas. AZA, 5-azacitidine; DAC, Decitabine; DNMT1, DNA methyltransferase 1; HDAC, Histone deacetylase; 2-HG, D-(R)-2-hydroxyglutarate; HMT, Histone methyltransferase; KDM, Histone demethylase; TET, Ten-eleven translocation methylcytosine dioxygenases; VPA, Valproic acid; 5mC, 5-Mehylcytosine. Me: Methyl group; Ac, Acetyl group.
Figure 2
Figure 2
Metabolic vulnerabilities in IDH-mutant gliomas and potential targets for single treatment or combination treatment with TMZ. Actionable metabolic dependencies in IDH-mutant gliomas include interrupted redox balance, low basal levels of glutamate, NAD+ and lipid synthesis. ASNS, Asparagine synthetase; BAF, Bafilomycin A1; CQ, Chloroquine; 2DG, 2-Deoxy-D-glucose; DNMS, N,N-dimethylsphingosine; ER, Endoplasmic reticulum; GLS, Glutaminase; IDH, Isocitrate dehydrogenase; NAD+, Nicotinamide adenine dinucleotide; NAMPT, Nicotinamide phosphoribosyl transferase; NAPRT, Nicotinate phosphoribosyltransferase; NRF2, nuclear factor erythroid 2-related factor; PARP, Poly (ADP-ribose) polymerse; PARG, Poly (ADP-ribose) glycohydrolase.
Figure 3
Figure 3
TMZ molecular structure, metabolism, toxicity, and resistance. (a) TMZ structure and metabolism, (b) DNA methylation upon TMZ, (c) DNA base mispair upon DNA methylation, (d) mechanism of TMZ toxicity with intact MMR, BER, and HR, (e) mechanism of TMZ resistance with functional MGMT and non-functional MMR. AIC, 4-Amino-5-imidazolecarboxamide; BER, Base-excision repair; HR, Homologous repair; MGMT, O6-methylguanine-DNA-methyltransferase; MMR, Mismatch repair; MLH, MutL homologue; MSH, MutS homologue; PMS, Post-meiotic segregation; TMZ, Temozolomide.
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