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.

Keywords: alkylating agents; brain tumor; glioblastoma; temozolomide (TMZ), triazene compounds.

Figure 1

Prodrug activation of TMZ and DTIC. DTIC requires oxidative N-demethylation via CYP450 enzymes, giving rise to HMTIC. HMTIC then eliminates formaldehyde and forms MTIC. TMZ, in contrast, is spontaneously hydrolyzed to MTIC at neutral or alkaline pH. Thereafter, DTIC and TMZ share the same pathway. MTIC further fragments to AIC and the methyldiazonium ion, which in turn reacts with nucleophilic sites, for example, in the DNA. In addition, DTIC can be activated by photolysis, yielding 2-azahypoxanthine. Abbreviations: AIC, 5-aminoimidazole-4-carboxamide; CYP450, cytochrome P450; DNA, deoxynucleic acid; DTIC, dacarbazine; HMTIC, 5,3-hydroxy,ethyl-3-methyl-triazene-imidazole-carboxamide; MTIC, 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide; TMZ, temozolomide. Based on [18,32].

Figure 2

TMZ-induced alterations and DNA repair mechanisms involved in cellular response. The methyldiazonium ion, a highly electrophilic ion, methylates nucleophilic sites in the DNA. Lack of BER or low MGMT levels in combination with functional MMR are required for cell death induction. Abbreviations: BER, base excision repair; DSB, double strand break; HR, homologous recombination; MGMT, methylguanine-DNA methyltransferase; MMR, mismatch repair; MTIC, 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide; NHEJ, non-homologous end joining; SSB, single strand break; TMZ, temozolomide. Based on [29,40,50].