ZD1839 Therapy of Glioblastoma Multiforme

ZD1839 多形性胶质母细胞瘤的治疗

• 批准号: 6515118
• 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/6515118
• 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）：尽管有数十年的密集 神经系统（CNS）肿瘤仍然很差。成人中位生存 CNS肿瘤的最常见形式，脑胶质母细胞瘤为8-12 诊断后的几个月。偶尔对单个或多个代理的响应 在复发性肿瘤的情况下可以看到化学疗法，但是这些反应 通常持续时间很短，疗法很少见。鉴定代理 活跃于神经胶质恶性肿瘤很具有挑战性，迄今为止尚无药物测试 在大多数治疗患者中可靠地产生反应。基因 已经发现与神经胶质瘤恶性肿瘤等级有关的扩增已被发现 大约50％的多形胶质母细胞瘤（GBM）发生 案例。尽管N-MYC和GLI的扩增（总体2-4％）是 由不同组报道，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 表皮生长因子（EGFR）基因。 EGFR基因，大小为110 kb，26个外显子 组织，本地化为染色体ARM 7PLL-13。以 Libermann等人（1985）对EGFR基因扩增的最初描述， 随后的研究证实，大约37-58％的GBMS，但 只有分离的偏长胶质细胞瘤，扩增EGFR基因。 ZD 1839是一个 EGFR酪氨酸激酶，与ATP竞争的有效抑制剂在体外 与肽底物非竞争。 ZD 1839抑制了 EGF刺激的KB口服鳞状癌细胞。这个效果很容易 在去除化合物时可逆。酶抑制似乎是 选择性，对其他激酶的活性很少。生长抑制 裸鼠中多种人类肿瘤异种移植模型的体内IS 每天一次以12.5至200 mg/kg的口服剂量证明 每天最多4个月。在一些已经建立的肿瘤治疗中 ZD 1839产生了重大回归。从异种移植研究中，不是 但是清楚的是EGFR表达水平和 抗肿瘤反应。该提案的具体目的是：1）确定 ZD 1839年对成人胶质母细胞瘤治疗的活性和毒性 在第一复发中多形； 2）确定定性和定量是否 基因型和表型EGFR表达的水平预测了GBM对 ZD 1839。