PARP Inhibitors for Chemotherapy of Brain Tumors

用于脑肿瘤化疗的 PARP 抑制剂

• 批准号: 6740002
• 负责人: JIE ZHANG
• 金额: $ 10.7万
• 依托单位: GUILFORD PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-08 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740002
• 关键词: antineoplastics; brain neoplasms; chemical synthesis; disease /disorder model; dosage; drug design /synthesis /production; enzyme inhibitors; laboratory mouse; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pentosyltransferase; pharmacokinetics; temozolomide

DESCRIPTION (provided by applicant): The objective for the proposed study is to determine the feasibility of using novel small molecule poly(ADPribose) polymerase (PARP) inhibitors as an adjunct treatment to enhance the antitumor activities of chemotherapeutic agents, especially against metastatic malignancy in brain. Most cancer chemotherapies suffer from innate or treatment-induced resistance of neoplastic cells to cytotoxic agents. Inhibition of PARP, a key nuclear enzyme to facilitate DNA repair, has proved an effective way to increase the killing of tumors by DNA methylating agents such as temozolomide (TMZ) in rodents. In the past, lack of PARP inhibitors capable of penetrating the blood brain barrier hindered testing whether PARP inhibition could synergistically increase the efficacy of TMZ against CNS tumors such as glioma, metastatic melanoma ,and brain lymphoma. Now, Guilford Pharmaceuticals Inc. has identified a series of water-soluble PARP inhibitors that 1) achieved high-level accumulation in brain after intravenous dosing and 2) provided neuroprotection in a rat model of stroke. We intend to test our proprietary PARP inhibitors in murine models of CNS malignancy. In collaboration with Dr. Grazia Graziani (University of Rome), we demonstrated that our leading PARP inhibitor, GPI 15427, greatly increased the survival rate, life span, and decreased metastasis when the compound was used in combination with TMZ in mice with intracranially injected melanoma or lymphoma, or with xenographted glioma, in comparison to TMZ treatment alone. To achieve the objective of the current study, we have designed a series of experiments that are aimed at 1) optimizing the chemical properties of the GPI 15427 series compounds for "drug like" properties; 2) characterizing the pharmacokinetic and toxicological profiles of the GPI 15427; and 3) determine the optimal dose-effect relationship of the GPI 15427 series of compounds in mouse models of CNS malignancy. We expect results from this phase I study will yield information for assessing the prospect of a phase II preclinical development towards clinical trials and commercialization of PARP inhibitors as enhancers of chemotherapy.

描述（由申请人提供）：拟议研究的目的是确定使用新型的小分子聚（adpribose）聚合酶（PARP）抑制剂作为辅助治疗的可行性，以增强化学治疗剂的抗肿瘤活性，尤其是针对大脑转移性恶性肿瘤的抗肿瘤活性。大多数癌症化学疗法都具有先天或治疗诱导的肿瘤细胞对细胞毒性剂的抗性。抑制PARP是一种促进DNA修复的关键核酶，已证明是一种有效的方法，可以通过啮齿动物中的DNA甲基化剂（例如替莫唑胺（TMZ））增加肿瘤杀死肿瘤。过去，缺乏能够穿透血脑屏障的PARP抑制剂阻碍了测试是否可以协同提高TMZ对CNS肿瘤的疗效，例如神经胶质瘤，转移性黑色素瘤和脑淋巴瘤。现在，Guilford Pharmaceuticals Inc.已经确定了一系列水溶性PARP抑制剂，即1）静脉注射后在大脑中实现了大脑中的高级积累，2）在中风模型中提供了神经保护作用。我们打算在中枢神经系统恶性肿瘤模型中测试我们的专有PARP抑制剂。与Grazia Graziani博士（罗马大学）合作，我们证明了我们的领先PARP抑制剂GPI 15427大大提高了当与骨间注射蜂蜜瘤或淋巴瘤与Xenmaphome contymass complorision complorision complorision tonmoma相对，大大提高了该化合物与TMZ结合使用TMZ时的生存率，寿命和转移降低。为了实现当前研究的目标，我们设计了一系列实验，这些实验针对1）优化GPI 15427系列化合物的化学特性，用于“药物”特性； 2）表征GPI 15427的药代动力学和毒理学特征； 3）确定CNS恶性小鼠模型中GPI 15427系列化合物的最佳剂量效应关系。我们预计，这一I阶段研究的结果将产生信息，以评估II期临床前开发的前景，用于临床试验和PARP抑制剂作为化学疗法增强子的商业化。