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Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
Reply published on 20 April 2020, see Biomedicines 2020, 8(4), 93.
Open AccessComment

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

Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 65, D-55130 Mainz, Germany
Biomedicines 2019, 7(4), 90; https://doi.org/10.3390/biomedicines7040090
Received: 17 October 2019 / Revised: 2 November 2019 / Accepted: 5 November 2019 / Published: 11 November 2019
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called SN1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some researchers expressed doubt that data mostly obtained by in vitro models can be translated into the in vivo situation. In experimental settings, high doses of the agent are often used, which are likely to activate responses triggered by base N-alkylations instead of O6-methylguanine (O6MeG), which is the primary cytotoxic lesion induced by low doses of temozolomide and other methylating drugs in O6-methylguanine-DNA methyltransferase (MGMT) repair incompetent cells. However, numerous studies provided compelling evidence that O6MeG is not only a mutagenic, but also a powerful toxic lesion inducing DNA double-strand breaks, apoptosis, autophagy and cellular senescence. MGMT, repairing the lesion through methyl group transfer, is a key node in protecting cells against all these effects and has a significant impact on patient’s survival following temozolomide therapy, supporting the notion that findings obtained on a molecular and cellular level can be translated to the therapeutic setting in vivo. This comment summarizes the current knowledge on O6MeG-triggered pathways, including dose dependence and the question of thresholds, and comes up with the conclusion that data obtained on cell lines using low dose protocols are relevant and apoptosis, autophagy and senescence are therapeutically important endpoints. View Full-Text
Keywords: Temozolomide; alkylating agents; DNA repair; apoptosis; senescence Temozolomide; alkylating agents; DNA repair; apoptosis; senescence
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Kaina, B. 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. Biomedicines 2019, 7, 90.

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