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Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
Open AccessLetter

On the Critical Issues in Temozolomide Research in Glioblastoma: Clinically Relevant Concentrations and MGMT-independent Resistance

Department of Fundamental and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, The Ministry of Health of the Russian Federation, Kropotkinsky Lane 23, 119034 Moscow, Russia
Department of Medical Nanobiotechnologies, Medico-Biological Faculty, N.I. Pirogov Russian National Research Medical University, The Ministry of Health of the Russian Federation, Ostrovitianov Str. 1, 117997 Moscow, Russia
Author to whom correspondence should be addressed.
Biomedicines 2019, 7(4), 92;
Received: 11 November 2019 / Accepted: 25 November 2019 / Published: 27 November 2019
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
The current standard first-line treatment for adult patients with newly diagnosed glioblastoma includes concurrent radiotherapy and daily oral temozolomide (TMZ), followed by adjuvant TMZ. As a prodrug, TMZ undergoes spontaneous hydrolysis generating a methylating agent. O6-methylguanine is considered the most preponderant toxic damage mechanism at therapeutically relevant TMZ doses, whereas MGMT, which encodes the O6-methylguanine-DNA methyltransferase DNA repair enzyme, is the most relevant resistance mechanism. Speculations on clinically relevant TMZ concentrations, cytotoxic and cytostatic effects of TMZ, and resistance mechanisms exist in the literature. Here, we raise the following principal issues: What are the clinically relevant TMZ concentrations in glioma patients, and which TMZ-induced molecular lesion(s) and corresponding resistance mechanism(s) are important for TMZ therapeutic effects at clinically relevant concentrations? According to clinical data from patients with glioblastoma, the mean peak TMZ concentrations in the peritumoral tissue might be much lower (around 5 µM) than usually used in in vitro research, and may represent only 20% of systemic drug levels. According to in vitro reports, single-dose TMZ at concentrations around 5 µM have minimal, if any, effect on apoptosis and/or senescence of glioblastoma cell lines. However, the clinically relevant concentrations of TMZ are sufficient to radiosensitize both MGMT-positive and -negative cell lines in vitro. It is speculated that a single DNA repair protein, MGMT, is highly efficient in protecting cells against TMZ toxicity. However, an endogenous level of MGMT protein expression is not universally correlated with TMZ responsiveness, and MGMT-independent mechanisms of TMZ resistance exist. View Full-Text
Keywords: Glioblastoma; glioma; temozolomide resistance; O6-methylguanine-DNA methyltransferase Glioblastoma; glioma; temozolomide resistance; O6-methylguanine-DNA methyltransferase
MDPI and ACS Style

Stepanenko, A.A.; Chekhonin, V.P. On the Critical Issues in Temozolomide Research in Glioblastoma: Clinically Relevant Concentrations and MGMT-independent Resistance. Biomedicines 2019, 7, 92.

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