Malignant central nervous system (CNS) tumors are perhaps the most difficult and frustrating neoplasms to treat, in large part due to the sensitive site in which these 'lesions arise and grow. The role of chemotherapy in the treatment of both malignant glioma and medulloblastoma continues to evolve with modest (in glioma) to more appreciable (in medulloblastoma) successes but new challenges to overcome. The chloroethylnitrosourceas (CENUs) 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 of malignant glioma to BCNC or CCNU, the CENUs have only modestly altered survival for patients with malignant brain tumors. CENUs such as BCNU produce highly reactive 2-chloroethyl carbonium ions following hydrolysis which car bifunctionally alkylate and crosslink DNA, RNA and proteins via ethylene bridges. The anti-tumor activity of CENUs appears to be proportional to DNA interstrand crosslink (ICL) formation. Resistance to alkylating agents including CENUs is multifactorial, with a diverse spectrum of mechanisms observed in murine and human neoplasia. These mechanisms include removal of the initial CENUs-induced mono-adduct by 06 alkylguanine-DNA alkyltransferase or quenching of the mono-adduct by glutathione. However, CENU-induced DNA ICL are not susceptible to either AGT removal or glutathione quenching. Therefore, resistance to CENUs in tumor cells in which DNA ICL are formed must be due to alternative mechanisms other that AGT-or glutathione-tumor cell interactions. The hypothesis of this proposal is that: repair of DNA ICL is 5 major mechanism of resistance to chloroethylnitrosourceas in malignant glioma and medulloblastoma.
The specific aims of this proposal are: 1) Define molecular events mediating repair of BCNU-induced DNA ICL by human cell extracts; 2) Define the DNA repair pathways operational in removal of BCNU-induced DNA ICL; 3) Define the role of repair of BCNU-induced DNA ICL in mediating resistance; 4) To conduct Phase 1 and 2 trials of BCNU plus inhibitors of DNA ICL repair in patients with malignant glioma.
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