Chemotherapy has become a useful adjunct in the management of malignant gliomas. Although the most effective agents (Chloroethylnitrosoureas) achieve a response in 50%-60% of patients treated, the long term prognosis is still poor. Drug resistance is felt to play a large part in the failure rate. The objectives of this research proposal are to investigate mechanisms of nitrosourea resistance in brain tumors in the following approach:
Specific Aim 1 -- to test the hypothesis that BCNU resistance is related to the activity of the DNA repair enzyme. Alkyltransferase which removes DNA drug adducts, and, Specific Aim 2 -- to test the hypothesis that BCNU resistance may also occur by removal of the DNA crosslink via the excision repair process. Alkyltransferase (AT) levels will be compared with inherent BCNU sensitivity measured by a clonogenic stem cell assay (Specific AIM 1). DNA crosslinks will be quantified are related to AT activity. Adaptation via increased AT levels will be determined following repetitive drug exposure. AT inhibition will be performed to enhance cytotoxic crosslink formation which should coincide with the stem cell assay results. The repair of crosslinked DNA (Specific Aim 2) will be investigated and compared with unscheduled DNA synthesis (UDS). The kinetics of crosslink removal should correspond to UDS and implicate nucleotide excision repair as another drug resistance mechanism. Differences in AT activity and excision repair will be investigated in pediatric and adult brain tumors. The health related significance of the proposed research is: 1) to determine if DNA repair mechanisms confer BCNU resistance in brain tumors, and 2) can resistance be overcome through repair inhibition of drug-induced DNA damage. If adaptation to BCNU occurs from the proposed mechanisms, alternative chemotherapy scheduling routines could be developed to overcome or prevent drug resistance.
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