ANTICANCER DRUG DISCOVERY THAT TARGETS TUMOR HYPOXIA

针对肿瘤缺氧的抗癌药物的发现

• 批准号: 6889494
• 负责人: DALE G NAGLE
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889494
• 关键词: animal extract; antineoplastics; biological signal transduction; biotechnology; biotherapeutic agent; chemical structure function; drug discovery /isolation; enzyme linked immunosorbent assay; gene expression; high throughput technology; hypoxia; hypoxia inducible factor 1; inhibitor /antagonist; laboratory mouse; neoplastic cell; neoplastic growth; plant extracts; spectrometry; transcription factor

DESCRIPTION (provided by applicant): The objective of the proposed research is to identify and characterize small molecule natural product-derived regulators of tumor hypoxia. Solid tumors contain regions under low oxygen tension (hypoxia) and this lack of oxygen contributes to resistance to radiation treatment and chemotherapy. Hypoxia-associated treatment resistance can be caused directly through reduced cellular oxygen concentrations or indirectly through hypoxia-induced modifications in gene expression. Current efforts to overcome hypoxia target the direct effects of hypoxia. We propose a new approach that specifically targets this important indirect effect of hypoxia (alteration of tumor gene expression). The unique focus of this program is to identify and evaluate natural product-derived small molecules that target hypoxia-induced gene expression. A three-pronged approach that combines natural products chemistry with molecular biology will be employed to identify and investigate such small molecules. The first objective will involve isolating and determining the chemical structures of natural product-derived regulators of tumor hypoxia. Such regulators will target a number of processes that are unique to hypoxic tumor cells and key for tumor cell adaptation to hypoxia. A panel of high-throughput bioassays has been established to identify such regulators. Active compounds will be isolated through bioassay-guided fractionation and isolation, and their chemical structures elucidated using a combination of spectroscopic and spectrometric methods. Our group has established the proof of principle for this approach through preliminary research that has identified several potent new hypoxia inducible factor-1 (HIF-1) inhibitors. HIF-1 is a key transcription factor that activates the expression of survival genes under hypoxia. The second objective will identify target genes affected by newly identified active leads. Preliminary studies have revealed that natural product derived small molecules can either selectively inhibit hypoxic activation of HIF-1 or inhibit both hypoxic and chemical activation of HIF-1, depending upon the specific chemical class of each of inhibitor. Inhibition of HIF-1 activation is associated with reduction of the hypoxic induction of HIF-1 target gene vascular endothelial growth factor (VEGF), a potent initiator of tumor angiogenesis. Target genes will be identified by microarray analysis. The third objective will focus on biochemical and cell biological investigations of the mechanisms by which newly identified active natural products regulate hypoxic signaling. Accomplishing these objectives will provide drug leads and molecular probes that target tumor hypoxia and afford new insights into the intracellular pathways affected by these molecules.

描述（由申请人提供）：拟定研究的目的是鉴定和表征肿瘤缺氧的小分子天然产物衍生调节剂。实体瘤包含低氧张力（缺氧）区域，这种缺氧有助于抵抗放射治疗和化疗。缺氧相关的治疗抗性可以通过降低细胞氧浓度直接引起或通过基因表达中缺氧诱导的修饰间接引起。目前克服缺氧的努力针对缺氧的直接影响。我们提出了一种新的方法，专门针对这种重要的缺氧间接影响（肿瘤基因表达的改变）。 该计划的独特重点是识别和评估靶向缺氧诱导基因表达的天然产物衍生小分子。一个三管齐下的方法，结合天然产物化学与分子生物学将被用来识别和研究这样的小分子。第一个目标将涉及分离和确定肿瘤缺氧的天然产物衍生的调节剂的化学结构。这种调节剂将靶向许多缺氧肿瘤细胞特有的过程，这些过程是肿瘤细胞适应缺氧的关键。已经建立了一组高通量生物测定来鉴定这些调节剂。活性化合物将通过生物测定指导的分馏和分离进行分离，并使用光谱和光谱方法的组合来阐明其化学结构。我们的研究小组已经通过初步研究确定了几种有效的新的缺氧诱导因子-1（HIF-1）抑制剂，为这种方法建立了原理证明。HIF-1是一个关键的转录因子，在缺氧条件下激活生存基因的表达。第二个目标是确定受新发现的活性先导物影响的靶基因。初步研究表明，天然产物衍生的小分子可以选择性地抑制HIF-1的缺氧活化或抑制HIF-1的缺氧和化学活化，这取决于每种抑制剂的特定化学类别。HIF-1激活的抑制与HIF-1靶基因血管内皮生长因子（VEGF）的低氧诱导减少有关，VEGF是肿瘤血管生成的有效启动子。将通过微阵列分析鉴定靶基因。第三个目标将集中在新发现的活性天然产物调节缺氧信号的机制的生物化学和细胞生物学研究。实现这些目标将提供靶向肿瘤缺氧的药物先导物和分子探针，并为受这些分子影响的细胞内途径提供新的见解。