Malignant gliomas have an extremely poor prognosis with median survival rates of less than 2 years. Although most frequent in older adults, these tumors are the third leading cause of cancer deaths in persons 15 to 34 years of age. Alkylating agents, used in single agent or combination chemotherapy with surgery and radiation, are the most effective antitumor drugs for treatment of adult gliomas. However, intrinsic and acquired resistance limits their usefulness. Our broad, long term objective is to define the contribution of DNA repair mechanisms to glioma resistance to chemotherapeutic alkylating agents, and to identify strategies to combat resistance. We have shown that resistance of human gliomas to alkylating agents is based on a mechanism(s) in addition to the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Our overall hypothesis is that apurinic/apyrimidinic endonuclease (Ap endo), a DNA repair activity that removes cytotoxic, alkylation-induced abasic sites, contributes to human glioma alkylating agent resistance. Our preliminary data show that gliomagenesis is accompanied by elevation of Ap endo activity, and that activity is positively correlated with tumor characteristics associated with poor prognosis. To address our hypothesis, we will [1] determine the contribution of Ap endo to alkylator resistance in glioma cell with different DNA repair backgrounds, [2] determine the effects of endogenous oxidative stress on Ap endo activity and alkylator resistance, and [3] characterize the oxidative free radical-induced elevation of Ap endo and enhanced alkylator resistance that we have recently observed in human glioma cells. The latter studies may be significant for design of optimal alkylating agent protocols, especially when employed concurrently with radiotherapy. We will also [4] examine the relationship of activity with response to alkylating agent-based chemotherapy (time to tumor progression). Evidence for a contribution of Ap endo to resistance would identify a new target for anti-resistance strategies directed against Ape1/Ref-1 (the major human Ap endo), either alone or together with MGMT.
