ZD1839 Therapy of Glioblastoma Multiforme

描述(由申请者提供)：尽管经历了几十年的紧张 神经系统(CNS)肿瘤仍然很差。成人的中位生存期 最常见的中枢神经系统肿瘤是大脑胶质母细胞瘤，发病年龄为8-12岁 在确诊后几个月。对单个或多个代理的临时响应 化疗见于肿瘤复发的背景下，但这些反应 一般都是短期的，治愈的情况很少。代理人的识别 抗神经胶质细胞恶性肿瘤的药物具有挑战性，到目前为止还没有药物测试。 在大多数接受治疗的患者中产生可靠的反应。基因 已发现扩增与胶质瘤恶性程度的增加有关。 约50%的多形性胶质母细胞瘤(GBM) 案子。尽管N-myc和gli的扩增(总体为2%-4%) 不同研究小组报道，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基因全长110kb，26个外显子 组织，定位于染色体臂7pll-13。从一开始 Libermann等人对EGFR基因扩增的初步描述(1985)， 随后的研究证实，大约37%-58%的GBM，但 只有孤立的间变性星形细胞瘤才能扩增EGFR基因。ZD 1839是一款 体外有效的EGFR酪氨酸激酶抑制剂，与ATP竞争，以及 与多肽底物不竞争。ZD 1839抑制细胞增殖的实验研究 EGF刺激的KB口腔鳞癌细胞。这种效果是显而易见的。 在去除该化合物后可逆。酶抑制似乎是 选择性的，对其他测试的激酶几乎没有活性。生长抑制 在体内建立了多种人肿瘤裸鼠移植瘤模型。 每天口服一次，剂量在12.5至200毫克/公斤之间 每天最多4个月。在一些已经确定的肿瘤治疗中，使用 ZD 1839产生了显著的回归。从异种移植的研究来看，它不是 目前尚不清楚EGFR的表达水平与 抗肿瘤反应。这项建议的具体目的是：1)确定 ZD-1839治疗成人胶质母细胞瘤的活性和毒性 首次复发的多种形式；2)确定定性和定量 EGFR基因和表型表达水平预测GBM对 ZD 1839.

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.