Journal
FRONTIERS IN ONCOLOGY
Volume 2, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2012.00176
Keywords
alkyladenine-DNA glycosylase,Apel; apurinic endonuclease; DNA repair; treatment outcome; predictive marker
Categories
Funding
- NIH [CAI 04593, CA 109087, CA131658]
- Brain Tumor Research Fund in memory of Ro Jean Mount
Ask authors/readers for more resources
Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma (GBM). More recently, inclusion of temozolomide (TMZ), an orally administered methylating agent with low systemic toxicity, during and after radiotherapy has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O-6-methylguanine (O-6-meG) mediates GBM cell killing. Moreover, low or absent expression of O-6-methylguanine-DNA methyltransferase (MGMT), the sole human repair protein that removes O-6-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O-6-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA) and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O-6-meG, is mediated by the base excision repair (BER) pathway, and occurs independently of removal of O-6-meG.These observations indicate that BER activities are also potential targets for strategies to potentiate TMZ cytotoxicity. Here we review the evidence that 3-meA and abasic sites mediate killing of GBM cells. We also present in vitro and in vivo evidence that alkyladenine-DNA glycosylase, the sole repair activity that excises 3-meA from DNA, and Apel, the major human abasic site endonuclease, mediate TMZ resistance in GBMs and represent potential anti-resistance targets.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available