Ape1, oxidative stress and glioma alkylator resistance

描述（申请人提供）：恶性胶质瘤预后极差，中位生存率不到2年。虽然最常见于老年人，但这些肿瘤是15至34岁人群癌症死亡的第三大原因。烷基化剂是治疗成人胶质瘤最有效的抗肿瘤药物，用于单药或手术、放疗联合化疗。然而，固有的和后天的阻力限制了它们的用途。我们广泛的长期目标是确定DNA修复机制对胶质瘤对化疗烷基化剂耐药的贡献，并确定对抗耐药的策略。我们已经证明，除了DNA修复蛋白o6 -甲基鸟嘌呤-DNA甲基转移酶（MGMT）外，人类胶质瘤对烷基化剂的抗性还基于一种机制。我们的总体假设是，无嘌呤/无嘧啶核酸内切酶（Ap endo），一种DNA修复活性，去除细胞毒性，烷基化诱导的基本位点，有助于人类胶质瘤烷基化剂抗性。我们的初步数据显示，胶质瘤的形成伴随着Ap内切酶活性的升高，并且该活性与肿瘤特征呈正相关，与预后不良相关。为了验证我们的假设，我们将[1]确定具有不同DNA修复背景的胶质瘤细胞中Ap内do对烷基化剂抗性的贡献，[2]确定内源性氧化应激对Ap内do活性和烷基化剂抗性的影响，[3]表征氧化自由基诱导的Ap内do升高和烷基化剂抗性增强，我们最近在人类胶质瘤细胞中观察到。后一项研究可能对设计最佳的烷基化剂方案具有重要意义，特别是当与放疗同时使用时。我们还将研究活性与烷基化剂化疗反应（肿瘤进展时间）的关系。Ap endo对耐药性贡献的证据将确定针对Ape1/Ref-1（主要的人类Ap endo）的抗耐药性策略的新靶点，无论是单独还是与MGMT一起。

DESCRIPTION (provided by applicant): 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.