Glioblastoma vs temozolomide: can the red queen race be won?

Figures & data

Figure 1. Mechanism of action of temozolomide. Temozolomide is stable at acidic pH. At physiological pH, it is chemically converted to 5-(3-methyltriazol-1-yl)imidazole-4-carboxamide (MTIC, active compound. MTIC is further hydrolyzed to 5-amino-imidazole-4-methyl Amide (AIC) and methyldiazolium. Methyldiazo ions react with DNA and release its methyl group.

Figure 2. Adduct formation as a result of the reaction of DNA and temozolomide. A) N7 methylguanine (N7MG): The N7 position of guanine is methylated by temozolomide. The 70% adduct formed in the cells under temozolomide exposure was N7MG. B) N3 methyl adenine (N3MA): The N3 position of adenine is methylated by temozolomide. The 10% adduct formed in the cells under temozolomide exposure was N3MA. C) O6 methylguanine (O6MG): The O6 position of adenine is methylated by temozolomide. The 5% adduct formed in the cells upon exposure to temozolomide is O6MG.

Figure 3. Resistance mechanism of temozolomide. A) N7MG and N3MA induced base excision repair (BER) pathways leading to recognition of modified bases by DNA glycosylation enzymes followed by base excision by AP endonuclease. This results in the recruitment of complexes containing DNA polymerase, DNA ligase, and adaptor molecules. This complex replaces the damaged site with the correct foundation. An effective BER results in resistance to temozolomide. B) O6MG on DNA results in an O6MG-thymidine mismatch. In the presence of active mismatch repair (MMR), the incorporated thymine was removed from the undamaged strand and incorporated again during the next replication cycle. This results in an ineffective loop of MMR which results in cytotoxicity. In the absence of an active MMR mechanism, the O6MG-thymidine mismatch is tolerated and cells survive. In the presence of MGMT, the O6MG is repaired, resulting in resistance.

Box 1. Red queen race conversation from Alice in the wonderland by Lewis Carroll.

“Well, in our country,” Alice said, still panting. “You usually get to other places – if you run fast for a long time, as we have been doing.”

“A slow country!” said the Queen. “Now, here, you see, it requires all the runs you can do, stay in the same place. If you want to reach other places, you must run at least twice as fast as you have been doing!”.

Box 2. Methods for MGMT measurement.

The MGMT promoter methylation status is an important requirement test for gliomas for clinical decision making. The value of this test is that the state can be proven to be prognostic and predictive of the response to temozolomide. The MGMT gene consists of five exons and is located on chromosome 10q26. Most of the promoter and first exon consist of a stretch of CpG dinucleotide.^Citation50 The following tests were performed to measure the methylation status of the MGMT promoter:

Table

GBM	glioblastoma
MGMT	O6-methylguanine-DNA methyltransferase
MMR	mismatch repair
BER	base excision repair
N7MG	N7 methylguanine
N3MG	N3 methylguanine
O6BG	O6-benzylguanine

Bienkowski M, Berghoff AS, Marosi C, Wöhrer A, Heinzl H, Hainfellner JA, Preusser M. Clinical Neuropathology practice guide 5-2015: MGMT methylation pyrosequencing in glioblastoma: unresolved issues and open questions. Clin Neuropathol. 2015;34:250–257.

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