English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Plus monthly

Global: Zendy Tools annual

Global: Zendy Tools monthly

Global: Zendy Free Plan

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. O 6 -methylguanine is considered the most preponderant toxic damage mechanism at therapeutically relevant TMZ doses, whereas MGMT , which encodes the O 6 -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.

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