Glioblastoma is the most invasive form of brain tumor. Although temozolomide chemotherapy has been shown to significantly improve survival in patients with GBM, this increase is only trivial. The underlying cause is that many GBMs do not respond to temozolomide, and the rest produces resistance. In the past two decades, many attempts have been made to understand resistance mechanisms and to combine other treatments with temozolomide to maximize patient benefit. Unfortunately, it seems to be a red queen game, and the speed of disease development is as fast as the progress in the field. In order to win this game, a comprehensive approach is needed to decipher the details of the resistance mechanism and to transfer the basic research to the clinic. This article reviews the following: temozolomide discovery, chemistry, and mechanism of action, and mechanisms of resistance, as well as combination therapy with other strategies.
Keywords: BER; DNA repair; MGMT; MMR; Temozolomide; alkylating agents; chemoresistance; glioblastoma; glioma.