Ape1, oxidative stress and glioma alkylator resistance

描述(申请人提供)：恶性胶质瘤预后极差，中位存活率不到两年。虽然这些肿瘤在老年人中最常见，但在15至34岁的人中，它们是导致癌症死亡的第三大原因。烷化剂是目前治疗成人脑胶质瘤最有效的抗肿瘤药物，用于单药或联合化疗、手术和放射治疗。然而，内在的和后天的阻力限制了它们的用途。我们广泛而长期的目标是确定DNA修复机制在胶质瘤对化疗烷化剂耐药中的作用，并确定对抗耐药的策略。我们已经证明，人脑胶质瘤对烷化剂的抗药性除了DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)外，还有一个机制(S)。我们的总体假设是，脱嘌呤/脱嘧啶核酸内切酶(AP Endo)是一种DNA修复活性，可以去除细胞毒性的烷基化诱导的基本位点，与人脑胶质瘤的烷化剂耐药有关。我们的初步数据显示，胶质瘤的形成伴随着AP Endo活性的升高，并且这种活性与预后不良的肿瘤特征呈正相关。为了解决我们的假设，我们将[1]确定AP Endo对具有不同DNA修复背景的胶质瘤细胞的烷基化抗性的贡献，[2]确定内源性氧化应激对AP Endo活性和烷化抗性的影响，以及[3]表征我们最近在人脑胶质瘤细胞中观察到的氧化自由基诱导的AP Endo升高和烷化抗性增强。后一项研究可能对设计最佳的烷化剂方案具有重要意义，特别是当与放射治疗同时使用时。我们还将[4]检查活性与基于烷化剂的化疗反应(肿瘤进展时间)的关系。AP endo对耐药性的贡献的证据将为针对APE1/Ref-1(主要的人类AP endo)的抗耐药策略确定一个新的靶点，要么单独使用，要么与MGMT一起使用。

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.