DNA DAMAGE AND REPAIR IN BRAIN TUMORS

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Chloroethylnitrosoureas (CENUs) are a group of chemotherapeutic agents used in conjunction with radiation therapy for the treatment of brain tumors. The goal of our research is to investigate the roles of DNA damage and repair in the cellular response of brain tumors to treatment with these and other agents. The DNA repair enzyme O/6-alkylguanine-DNA alkyltransferase (O/6-AT) has been shown to play an important role in determining cellular resistance to CENUs, although its role in determining the response of tumors to treatment with CENUs has not been determined. In addition, the extent of DNA damage in the lymphocytes of patients undergoing treatment with CENUs may be an indicator of the extent of DNA damage in the tumor being treated. We propose that measurement of the levels of O/6-AT in surgical glioma specimens and of DNA alkylation in patients' lymphocytes after treatment with CENUs may be useful indicators of patients' responses to the treatment. In parallel the halogenated pyrimidines 5-bromo-2'deoxyuridine (bromodeoxyuridine; BUdR) and 5-iodo- 2'deoxyuridine (iododeoxyuridine; IUdR) are well-established radiosensitizers in vitro. For the successful use of these agents as radiosensitizers in the treatment of patients with brain tumors, an understanding of their incorporation into DNA is required. To better understand the relationships between DNA damage and repair and response to treatment with CENUs and radiosensitizers, our specific aims are: 1) to measure the level of O/6-AT in primary brain tumors and determine whether increased O/6-AT levels correlate inversely with clinical efficacy of treatment with nitrosoureas; 2) to compare the levels of O/6-AT in primary and recurrent brain tumors; 3) to measure the levels of N/7-(2- hydroxyethyl)guanine and N/7-(2-chloroethyl)guanine in DNA isolated from lymphosytes of patients treated with l,3,bis(2-chloroethyl)-1-nitrosourea (BCNU); 4) to develop and apply the 32/P-postlabeling technique for the detection of the cross-link 1-[N/3-2'deoxycytidyl], 2-[N/1- deoxyguanosinyl]-ethane in DNA isolated from the lymphocytes of patients treated with BCNU; 5) to determine whether the levels of N/7-2- hydroxyethyl)guanine and N/7-(2-chloroethyl)guanine and 1-[N/3- 2'deoxycytidyl], 2-[N/1-deoxyguanosinyl]-ethane correlate with clinical efficacy of treatment with nitrosoureas; and, 6) to measure the percent substitution of BUdR and IUdR for thymidine in brain tumors.