A series of 3-(benzyl-substituted)-imidazo[5,1-<i>d</i>]-1,2,3,5-tetrazines (<b>13</b>) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity <i>in vitro</i> against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase (MGMT).
High level of DNA repair protein, O<sup>6</sup>-methylguanine-DNA-methyltransferase (MGMT) and occurrence of glioma stem-like cells contribute to GBM resistance to the drug.
DNA repair protein O<sup>6</sup>-methylguanine-DNA methytransferase (MGMT) plays a key role in TMZ resistance; transcription factor specificity protein 1 (SP1), a regulator of DNA mismatch repair (MMR) key protein MSH6, has been reported to be up-regulated in TMZ-resistant glioma cell lines.
The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) causes resistance of cancer cells to alkylating agents and, therefore, is a well-established predictive marker for high-grade gliomas that are routinely treated with alkylating drugs.
We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas.