GENE THERAPY TARGETING HYPOXIC GLIOMA CELLS

针对缺氧神经胶质瘤细胞的基因治疗

• 批准号: 6837142
• 负责人: DENNIS F. DEEN
• 金额: $ 31.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837142
• 关键词: Bax gene /protein; adeno associated virus group; aminohydrolases; clinical research; combination cancer therapy; gene therapy; glioma; human subject; hypoxia; immunocytochemistry; laboratory rat; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; radiation genetics; recombinant virus; transcription factor; transfection /expression vector; western blottings

Radiation is a primary treatment modality for patients with malignant gliomas, and in most patients radiation therapy is clearly beneficial. However, the overall outcome of therapy for these patients is dismal, and most patients with glioblastoma multiforme (GBM) die within a year of diagnosis. The presence of hypoxic cells in brain tumors is a major obstacle for radiation therapy, because these cells are notoriously resistant to radiation-induced damage. Therefore, we propose to devise a gene therapy approach for killing hypoxic brain tumor cells during the course of radiation therapy. The DNA construct to be delivered to the tumor cells contains hypoxia-responsive elements (HREs) in the enhancer region of the promoter and a suicide gene. Under hypoxic conditions, the transcriptional complex hypoxia inducible factor-1 (HIF- 1) builds up in cells and binds to HREs. This, in turn, activates the adjacent promoter and causes expression of the downstream suicide gene that kills the cell. This project has 2 goals. The first is to investigate how several cellular or intratumoral characteristics impact on this gene therapy strategy. The second is to investigate whether the gene therapy enhances the radiation response of the tumor cells. We propose 4 specific aims to accomplish these goals. 1) investigate the relationship between HIF-1 and oxygenation status in brain tumor and normal brain; 2) evaluate suicide genes under low pH and in noncycling brain tumor cells; 3) reveal and investigate any bystander effect (BE) produced by specific suicide genes under hypoxic conditions; 4) determine whether expression of suicide genes in hypoxic and oxic cells enhances their response to radiation.

放射治疗是恶性胶质瘤患者的主要治疗方式，对于大多数患者，放射治疗显然是有益的。然而，这些患者的总体治疗结果令人沮丧，大多数多形性胶质母细胞瘤（GBM）患者在诊断后一年内死亡。脑肿瘤中缺氧细胞的存在是放射治疗的主要障碍，因为这些细胞对放射引起的损伤具有很强的抵抗力。因此，我们建议设计一种基因治疗方法，在放射治疗过程中杀死缺氧的脑肿瘤细胞。递送至肿瘤细胞的 DNA 构建体在启动子增强子区域含有缺氧反应元件 (HRE) 和自杀基因。在缺氧条件下，转录复合物缺氧诱导因子 1 (HIF-1) 在细胞中积聚并与 HRE 结合。这反过来又激活相邻的启动子并导致下游自杀基因的表达，从而杀死细胞。该项目有 2 个目标。首先是研究几种细胞或肿瘤内特征如何影响这种基因治疗策略。第二个是研究基因治疗是否增强肿瘤细胞的放射反应。我们提出了 4 个具体目标来实现这些目标。 1）研究脑肿瘤和正常脑组织中HIF-1与氧合状态的关系； 2) 评估低pH条件下和非循环脑肿瘤细胞中的自杀基因； 3）揭示并研究特定自杀基因在低氧条件下产生的旁观者效应（BE）； 4) 确定缺氧和含氧细胞中自杀基因的表达是否增强其对辐射的反应。

项目成果

Retro-convection enhanced delivery to increase blood to brain transfer of macromolecules.

逆向对流增强输送，以增加大分子从血液到大脑的转移。

• DOI: 10.1016/j.brainres.2006.10.041
• 发表时间: 2007
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Huynh,GraceH;Ozawa,Tomoko;Deen,DennisF;Tihan,Tarik;SzokaJr,FrancisC
• 通讯作者: SzokaJr,FrancisC

Detection of hypoxia in human brain tumor xenografts using a modified comet assay.

使用改良的彗星测定检测人脑肿瘤异种移植物中的缺氧。

• DOI: 10.1016/s1476-5586(03)80022-2
• 发表时间: 2003
• 期刊: Neoplasia (New York, N.Y.)
• 作者: Wang,Jingli;Klem,Jack;Wyrick,JanB;Ozawa,Tomoko;Cunningham,Erin;Golinveaux,Jay;Allen,MaxJ;Lamborn,KathleenR;Deen,DennisF
• 通讯作者: Deen,DennisF

Growth of human glioblastomas as xenografts in the brains of athymic rats.

• 发表时间: 2002
• 期刊: In vivo
• 影响因子: 2.3
• 作者: T. Ozawa;Jinglian Wang;Lily J. Hu;A. Bollen;K. Lamborn;D. Deen