ZD1839 Therapy of Glioblastoma Multiforme

ZD1839 多形性胶质母细胞瘤的治疗

• 批准号: 6339953
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 32.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6339953
• 关键词: antineoplastics; enzyme activity; enzyme inhibitors; epidermal growth factor; flow cytometry; glioblastoma multiforme; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; magnetic resonance imaging; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; patient oriented research; polymerase chain reaction; protein tyrosine kinase; receptor expression

DESCRIPTION (Provided by applicant): Despite decades of intensive nervous system (CNS) neoplasms remains very poor. Median survival for adults with the most common form of CNS tumor, the cerebral glioblastoma, is 8-12 months after diagnosis. Occasional responses to single or multiple agent chemotherapy are seen in the setting of recurrent tumor, but these responses are generally of short duration, and cures are rare. Identification of agents active against glial malignancies is challenging, with no drug tested to date reliably producing responses in a majority of treated patients. Gene amplification, related to increasing grade of glioma malignancy, has been found to occur in approximately 50 percent of all glioblastoma multiforme (GBM) cases. Although amplification of N-myc and gli (2-4 percent overall) has been reported by different groups, amplification of these genes and c-myc or K-ras are considered sporadic as compared to the amplification of c-erb 1, or the epidermal growth factor (EGFR) gene. The EGFR gene, 110 kb in size, 26 exons in organization, is localized to chromosome arm 7pll-13. Beginning with the initial description of EGFR gene amplification by Libermann et al (1985), subsequent studies have confirmed that approximately 37-58 percent of GBMs, but only isolated anaplastic astrocytomas, amplify the EGFR gene. ZD 1839 is a potent inhibitor in vitro of EGFR tyrosine kinase, competitive with ATP, and noncompetitive with peptide substrate. ZD 1839 inhibits the proliferation of EGF-stimulated KB oral squamous carcinoma cells. This effect is readily reversible on removal of the compound. Enzyme inhibition appears to be selective, with little activity against other kinases tested. Growth inhibition in vivo of a wide variety of human tumour xenograft models in nude mice was demonstrated at a range of once daily, oral doses between 12.5 and 200 mg/kg per day for up to 4 months. In some already established tumours treatment with ZD 1839 produced significant regressions. From the xenograft studies, it is not yet clear if there is a correlation between the level of EGFR expression and antitumor response. The specific aims of this proposal are: 1) To identify the activity and toxicity of ZD 1839 in the treatment of adults with glioblastoma multiforme in first relapse; 2) to determine if qualitative and quantitative levels of genotypic and phenotypic EGFR expression predict response of GBM to ZD 1839.

描述（由申请人提供）：尽管经过数十年的强化 神经系统（CNS）肿瘤的情况仍然很差。成人中位生存期 最常见的中枢神经系统肿瘤，脑胶质母细胞瘤，是 8-12 诊断后几个月。对单个或多个代理的偶尔响应 化疗常见于肿瘤复发的情况，但这些反应 通常持续时间很短，治愈方法也很少见。代理人身份识别 积极对抗神经胶质恶性肿瘤具有挑战性，迄今为止还没有药物经过测试 在大多数接受治疗的患者中可靠地产生反应。基因 已发现与神经胶质瘤恶性程度增加有关的扩增 约 50% 的多形性胶质母细胞瘤 (GBM) 发生 案例。尽管 N-myc 和 gli 的扩增（总体 2-4%）已被 由不同小组报告，这些基因和 c-myc 或 K-ras 的扩增 与 c-erb 1 的扩增相比，被认为是零星的，或者 表皮生长因子（EGFR）基因。 EGFR基因，大小110 kb，26个外显子 组织，定位于染色体臂 7pll-13。开始于 Libermann 等人 (1985) 对 EGFR 基因扩增的初步描述， 随后的研究证实，大约 37-58% 的 GBM 存在，但 仅孤立的间变性星形细胞瘤，扩增EGFR基因。 ZD 1839 是 体外有效的 EGFR 酪氨酸激酶抑制剂，与 ATP 竞争，并且 与肽底物不具有竞争性。 ZD 1839 抑制增殖 EGF 刺激的 KB 口腔鳞状癌细胞。这个效果很容易实现 去除化合物后可逆。酶抑制似乎是 具有选择性，对其他测试的激酶几乎没有活性。生长抑制 在裸鼠体内建立了多种人类肿瘤异种移植模型 每日一次，口服剂量范围为 12.5 至 200 mg/kg 每天一次，持续长达 4 个月。在一些已经建立的肿瘤治疗中 ZD 1839 产生了显着的回归。从异种移植研究来看，并非如此 尚不清楚 EGFR 表达水平与 抗肿瘤反应。该提案的具体目标是： 1) 确定 ZD 1839 治疗成人胶质母细胞瘤的活性和毒性 首次复发时为多形性； 2）确定是否定性和定量 EGFR 基因型和表型表达水平可预测 GBM 的反应 ZD 1839。