The prognosis of patients with malignant glioma remains dismal, with conventional treatment with surgery, radiotherapy and alkylnitrosourea-based chemotherapy failing to cure all patients with glioblastoma multiforme and the majority of patients with anaplastic astrocytoma. Review of clinical trials for treatment of malignant glioma indicate that a major impediment to further progress is the emergence of drug-resistant tumor cells. Methylating agents are one of the two """"""""gold"""""""" standards (the other being nitrosoureas) for the treatment of malignant glioma. Temodar (temozolomide) is an imidazole tetrazinone whose mechanism of action is similar to that of dacarbazine, specifically via metabolic conversion to a common active intermediate, the methylating agent MTIC. Clinical trials suggest that Temodar has activity in the treatment of patients with newly diagnosed and recurrent high-grade glioma. Nevertheless it is clear that a cohort of patients with this tumor will fail Temodar. A series of studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that at least two mechanisms of resistance appear to be operational in mediating resistance to Temodar, O 6 -alkylguanine-DNA alkyltransferase (AGT) and DMA mismatch repair deficiency. The hypotheses of this proposal are 1) AGT and DNA mismatch repair deficiency play a role in mediating Temodar resistance in malignant glioma and medulloblastoma; 2) other mechanisms are also critical in mediating this resistance; and 3) inhibition of base excision repair can enhance Temodar activity.
The specific aims of this proposal are: 1) to define the role of AGT and AGT mutations in mediating resistance in tumors resected from patients with Temodar resistant malignant glioma; 2) to define the role of DNA mismatch repair deficiency in tumors resected from patients with Temodar resistant malignant glioma; and 3) to define the role of base excision repair (BER) in mediating resistance to tumors resected from patients with Temodar resistant malignant glioma and the role of inhibition of BER in enhancing Temodar activity in malignant glioma.
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