ANTICANCER DRUG DISCOVERY THAT TARGETS TUMOR HYPOXIA

针对肿瘤缺氧的抗癌药物的发现

基本信息

批准号：
7056196
负责人：
DALE G NAGLE
金额：
$ 25.85万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
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

项目摘要

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）：拟议的研究的目的是识别和表征肿瘤缺氧的小分子自然产物衍生的调节剂。实体瘤含有低氧张力（缺氧）下的区域，缺乏氧气有助于耐药性治疗和化学疗法。与缺氧相关的治疗抗性可以直接通过降低的细胞氧浓度或通过缺氧诱导的基因表达修饰而间接引起。当前克服缺氧的努力针对缺氧的直接影响。我们提出了一种新方法，该方法专门针对缺氧的这种重要间接作用（肿瘤基因表达的改变）。该程序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的小分子。将使用天然产物化学与分子生物学结合的三管齐下的方法将采用用于识别和研究此类小分子。第一个目标将涉及分离和确定肿瘤缺氧的天然产物衍生调节剂的化学结构。这样的调节剂将针对多个是缺氧肿瘤细胞独有的过程，以及肿瘤细胞适应低氧的关键。已经建立了一组高通量生物测定面板，以识别此类调节器。活性化合物将通过生物测定指导的分馏和分离来分离，并使用光谱和光谱法的组合阐明了它们的化学结构。我们的小组通过初步研究确定了几种有效的新缺氧诱导因子-1（HIF-1）抑制剂，为这种方法建立了原理证明。 HIF-1是在缺氧下激活生存基因表达的关键转录因子。第二个目标将确定受新确定的活跃铅影响的靶基因。初步研究表明，衍生的小分子可以选择性地抑制HIF-1的低氧激活或抑制HIF-1的低氧和化学激活，这取决于每个抑制剂的特定化学类别。 HIF-1激活的抑制与减少HIF-1靶基因血管内皮生长因子（VEGF）的低氧诱导有关，这是肿瘤血管生成的有效启动因子。靶基因将通过微阵列分析确定。第三个目标将重点介绍新鉴定的活性天然产物调节低氧信号传导的机制的生化和细胞生物学研究。实现这些目标将提供靶向肿瘤缺氧的药物铅和分子探针，并为受这些分子影响的细胞内途径提供新的见解。