Cargando…

Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 m...

Descripción completa

Detalles Bibliográficos
Autores principales: Strobel, Hannah, Baisch, Tim, Fitzel, Rahel, Schilberg, Katharina, Siegelin, Markus D., Karpel-Massler, Georg, Debatin, Klaus-Michael, Westhoff, Mike-Andrew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783999/
https://www.ncbi.nlm.nih.gov/pubmed/31505812
http://dx.doi.org/10.3390/biomedicines7030069
_version_ 1783457654256959488
author Strobel, Hannah
Baisch, Tim
Fitzel, Rahel
Schilberg, Katharina
Siegelin, Markus D.
Karpel-Massler, Georg
Debatin, Klaus-Michael
Westhoff, Mike-Andrew
author_facet Strobel, Hannah
Baisch, Tim
Fitzel, Rahel
Schilberg, Katharina
Siegelin, Markus D.
Karpel-Massler, Georg
Debatin, Klaus-Michael
Westhoff, Mike-Andrew
author_sort Strobel, Hannah
collection PubMed
description The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.
format Online
Article
Text
id pubmed-6783999
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-67839992019-10-16 Temozolomide and Other Alkylating Agents in Glioblastoma Therapy Strobel, Hannah Baisch, Tim Fitzel, Rahel Schilberg, Katharina Siegelin, Markus D. Karpel-Massler, Georg Debatin, Klaus-Michael Westhoff, Mike-Andrew Biomedicines Review The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences. MDPI 2019-09-09 /pmc/articles/PMC6783999/ /pubmed/31505812 http://dx.doi.org/10.3390/biomedicines7030069 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Strobel, Hannah
Baisch, Tim
Fitzel, Rahel
Schilberg, Katharina
Siegelin, Markus D.
Karpel-Massler, Georg
Debatin, Klaus-Michael
Westhoff, Mike-Andrew
Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title_full Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title_fullStr Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title_full_unstemmed Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title_short Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
title_sort temozolomide and other alkylating agents in glioblastoma therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783999/
https://www.ncbi.nlm.nih.gov/pubmed/31505812
http://dx.doi.org/10.3390/biomedicines7030069
work_keys_str_mv AT strobelhannah temozolomideandotheralkylatingagentsinglioblastomatherapy
AT baischtim temozolomideandotheralkylatingagentsinglioblastomatherapy
AT fitzelrahel temozolomideandotheralkylatingagentsinglioblastomatherapy
AT schilbergkatharina temozolomideandotheralkylatingagentsinglioblastomatherapy
AT siegelinmarkusd temozolomideandotheralkylatingagentsinglioblastomatherapy
AT karpelmasslergeorg temozolomideandotheralkylatingagentsinglioblastomatherapy
AT debatinklausmichael temozolomideandotheralkylatingagentsinglioblastomatherapy
AT westhoffmikeandrew temozolomideandotheralkylatingagentsinglioblastomatherapy