Biological Responses of Glioma Cell to Chemotherapeutic Agents

Because gliomas are not curable surgically, development of effective adjuvant therapies is warranted. A chemotherapeutic agent temozolimide (TMZ) has been widely used not only because it is well tolerated and easily administrated orally but because various clinical trials had revealed that high grade gliomas could show objective response or stable disease to this compound (Stupp et al., 2005). The action of TMZ had been extensively studied primarily in leukemia and lymphoma cells. TMZ spontaneously decomposes in aqueous solution to form the cytotoxic methylating agent, and the cytotoxicity of TMZ appears to be mediated mainly through adduction of a methyl group to O6 position of guanine (G) in genomic DNA. The methyl group can be removed from O6-methylguanine by O6-methylguanine-DNA methyltransferase (MGMT). If MGMT is deficient in the cell, however, O6-methylguanine is not repaired, and incorporation of a thymine (T) rather than a cytosine opposite the O6methylguanine during the next cycle of DNA replication leads to the formation of GT mismatches in DNA. This triggers the DNA mismatch repair (MMR) system which removes the T, only to have the T reinserted during repair synthesis. Futile cycles of MMR triggered by GT mismatches can lead to a variety of outcomes in TMZ-treated cells (Figure 1).