Management of malignant glioma in the temozolomide era

With the introduction of temozolomide (TMZ), a drug treatment for malignant gliomas has been developed and the importance of chemotherapy has been validated. Nonetheless, these tumors are still incurable, and many issues remain to be solved. Recent advances in tumor genetics have enabled us to better predict each patient's prognosis, and, especially in the TMZ era, methylation of the O^6-methylguanine-DNA methyltransferase (MGMT) promoter has been thoroughly investigated. This DNA repair enzyme catalyzes the O^6-methylguanine that TMZ creates and theoretically promotes TMZ resistance, and clinical studies have revealed that MGMT-proficient gliomas indeed showed a poorer prognosis. Thus many studies were carried out in an effort to inhibit MGMT in gliomas and to overcome TMZ resistance, but unfortunately, none have yielded a successful result, which leads to the conclusion that TMZ-resistance is not promoted solely by MGMT. Since medical treatment for malignant gliomas using DNA damaging agents could show limited efficacy, a new concept of molecular-targeted therapy has been developed. However, clinical studies using various molecular-targeted compounds did not make remarkable improvement in patients' prognosis either. New problems that have emerged from various clinical studies are discussed in this text to open novel prospects for medical treatment of malignant gliomas.