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Page 417 Gutierrez et al. Cancer Drug Resist 2021;4:414-23 I http://dx.doi.org/10.20517/cdr.2020.113

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Figure 4. O methylguanine:thymine base pairing that leads to G→A mutation. The pairing is based on data from the crystal structure
[8]
of the pair in oligodeoxyribonucleotides . Note that the thymine tautomer formed is not the standard tautomer drawn for thymine in
Watson-Crick base pairs.
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Persistent O methylguanine lesions and cell death
When replication is finished, the base pair depicted in Figure 4 can be recognized by an active MMR
pathway. If the MMR pathway removes the thymine, another thymine could be reinserted in a futile repair
process. Repeated futile repair cycles eventually result in the cell undergoing apoptosis [Figure 2].

Although MGMT inhibitors can deplete MGMT activity, another way to reduce the MGMT levels is to
take advantage of the variations in the levels of MGMT found in different cells. In many tumors, MGMT
deficiency is linked to epigenetic methylation of the MGMT promoter region to produce 5-methylcytosines
that silence expression [9-11] . MGMT promoter silencing is frequently found in tumors [12,13] . Tumors with low
MGMT levels usually produce positive patient outcomes.

Alternatives to silencing MGMT expression in tumors have used drugs, such as O6-benzylguanine, which
deplete MGMT protein levels by inactivating the protein. These MGMT inhibitors inactivate the protein
and are still undergoing clinical evaluation. One potential consideration for the poor outcomes using
MGMT inactivation is that drugs that deplete MGMT could also require other DNA repair systems, as
noted for the futile repair cycles.

Resistance to alkylating agent damage by MGMT
The levels of MGMT in tissues and in tumors vary greatly [14,15] . Tumors with low or MGMT-deficiency
respond better to dacarbazine or temozolomide therapy than do tumors with MGMT levels similar to
those found in normal cells [16-21] . Therefore, tumors with MGMT levels approximating those of normal cells
are more resistant to alkylating agent treatment. Conversely, tumors with low MGMT levels respond more
favorably to treatment as compared to tumors with normal MGMT levels [17,22-24] . Thus, improved outcomes
for patients with lower MGMT levels indicate that normal MGMT levels provide resistance to dacarbazine
or temozolomide treatment.

Resistance to alkylating agent damage by MGMT in concert with mismatch repair
MGMT protects against alkylating agent damage, and the discovery that tumors and cell lines can
spontaneously have the MGMT promoter silenced, certainly suggested that there could be cumulative
effects that would result in further sensitization of tumors to alkylating agent treatments. The MMR system