Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

Abstract

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.

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

“…It was further concluded that "TMZ should be considered primarily cytostatic and senescence-inducing and not cytotoxic and apoptosis-inducing, potentially preventing cancer cells from G2 to M phase transition when tumor cells are most sensitive for mitotic cell death." [1]. In my opinion, these are misleading and unsubstantiated statements that need comment.…”

“…In a recent review in Biomedicines, Strobel et al discussed the mode of action of temozolomide, which is being used first-line in glioblastoma therapy [1]. Temozolomide (TMZ, Temodal ® ) is a spontaneously decomposing methylating agent, which acts similarly to dacarbazine (DTIC) that needs metabolic activation.…”

Coronarin D Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Glioblastoma Cell Line

“…The addition of TMZ to the standard treatment protocol was hailed as a major breakthrough in GBM therapy. Despite this, patients' prognosis remains dismal with a five-year overall survival below 10% [11]. For this reason, more efficient therapeutic approaches are required for enhancing the treatment effect [12].…”

Revealing the epigenetic effect of temozolomide on glioblastoma cell lines in therapeutic conditions

“…Consequently, the currently accepted mechanism of resistance to TMZ is the activity of O 6 -methylguanine DNA methyltransferase (MGMT), the DNA repair enzyme [6]. However, in the light of numerous TMZ effects in the cell, cannot be the only one [16].The site of TMZ action (brain) requires its effective entrance into the central nervous system (CNS) through the blood brain barrier (BBB). That is achieved with the unique chemical structure as well as pharmacokinetic properties [18,19].…”

“…Consequently, the currently accepted mechanism of resistance to TMZ is the activity of O 6 -methylguanine DNA methyltransferase (MGMT), the DNA repair enzyme [6]. However, in the light of numerous TMZ effects in the cell, cannot be the only one [16].…”