AGT DEPLETION FOR THERAPY OF CNS TUMORS
Principal Investigator: Jennifer A Quinn
Abstract: 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. This failure is due almost exclusively to de novo or acquired resistance to chemotherapy with subsequent tumor growth and patient death. The nitrosoureas and methylators such as procarbazine were originally chosen for treatment of central nervous system tumors on the basis of favorable physiochemical properties such as lipophilicity as well as activity against L1210 leukemia cells growing intracranially in mice. Nevertheless, despite moderate sensitivity to malignant glioma to BCNU or lomustine, the nitrosoureas have not dramatically altered survival for patients with malignant brain tumors. This situation presumably reflects de novo or acquired intrinsic cellular resistance rather than restricted delivery to the intracranial site. The major mechanism of resistance to alkylnitrosourea and methylator therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). AGT removes chlorethylation or methylation damage from the O6-position of guanine prior to cell injury and death. The high incidence of AGT activity in human central nervous system tumors, as well as the inverse relationship between procarbazine activity and alkyltransferase levels in human brain tumor xenografts, supported a role for this protein in mediating resistance to nitrosoureas in patients with CNS tumors and provided an approach for reversal of drug resistance. Furthermore three recent clinical trials have suggested that AGT levels in patients receiving BCNU therapy correlate with outcome. The hypothesis of this proposal are 1) AGT plays a critical role in mediating resistance of malignant glioma to nitrosoureas and methylators and 2) O6-benzylguanine (O6-BG) mediated reduction of glioma AGT levels can enhance nitrosourea (BCNU) and methylator (temozolomide) treatment of these tumors. The specific aims of this proposal are 1) to further define the toxicity of BCNU + O6- BG and temozolomide + O6-BG respectively, in the treatment of adults with malignant glioma; 2) to define the activity and subsequently efficacy of BCNU +06-BG and temozolomide and O6-BG respectively, in the treatment of adults with malignant glioma.
Funding Period: 2000-09-30 - 2005-08-31
more information: NIH RePORT