Authors:	Beltzig, Lea Stratenwerth, Björn Kaina, Bernd
Title:	Accumulation of temozolomide-induced apoptosis, senescence and DNA damage by metronomic dose schedule : a proof-of-principle study with glioblastoma cells
Online publication date:	13-Feb-2023
Year of first publication:	2021
Language:	english
Abstract:	Temozolomide (TMZ), a first-line drug in glioma therapy, targets the tumor DNA at various sites. One of the DNA alkylation products is O6-methylguanine (O6MeG), which is, in the low dose range of TMZ, responsible for nearly all genotoxic and cytotoxic effects relevant for cancer therapy. There is, however, a dispute regarding whether the TMZ concentration in the tumor tissue in patients is sufficient to elicit a significant cytotoxic or cytostatic response. Although treatment with TMZ occurs repeatedly with daily doses (metronomic dose schedule) and in view of the short half-life of the drug it is unclear whether doses are accumulating. Here, we addressed the question whether repeated low doses elicit similar effects in glioblastoma cells than a high cumulative dose. We show that repeated treatments with a low dose of TMZ (5 × 5 µM) caused an accumulation of cytotoxicity through apoptosis, cytostasis through cellular senescence, and DNA double-strand breaks, which was similar to the responses induced by a single cumulative dose of 25 µM TMZ. This finding, together with the previously reported linear dose–response curves, support the notion that TMZ is able to trigger a significant cytotoxic and cytostatic effect in vivo if the low-dose metronomic schedule is applied.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8667
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Cancers 13 24
Pages or article number:	6287
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2021
ISSN:	2072-6694
Publisher DOI:	10.3390/cancers13246287
Appears in collections:	JGU-Publikationen