Molecular design of hypoxia-targeting anticancer drug.

缺氧靶向抗癌药物的分子设计。

基本信息

批准号：
14580611
负责人：
NAGASAWA Hideko
金额：
$ 2.3万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580611/
关键词：
hypoxic cytotoxin HIF-1α angiogenic inhibition hypoxia apoptosis HIF-1α 低酸素細胞 HIF-1 VEGF がん微小環境 p53

项目摘要

Background : Hypoxia represents an important tumor-specific target for cancer therapy. We have reported that hypoxic cytotoxins, such as TX-1102, tirapazamine (TPZ) and TX-402, selectively induced tumor cells to p53-independent apoptosis under hypoxic conditions and inhibited angiogenesis.Method : We investigated the effects of the antiangiogenic hypoxic cytotoxins on hypoxia-induced gene expression and th6ir hypoxia-selective cytotoxicity in human squamous cell carcinoma of the head and neck (SAS cells) and p53-deficient human non-small cell lung carcinoma H1299 cells transfected with either wild-type or mutantp53 gene.Results : TX-402 had more potent hypoxia-selective cytotoxicity. than TPZ in either cell regardless of p53 status. All the compounds inhibited angiogenesis potently at doses of more than 5 μg/CAM in chick embryo chorioallantoic membrane (CAM) assay. RT-PCR analyses indicated that TX-402 reduced the inducible expression of vascular endothelial cell growth factors (VEGE) and glucose transporter type 3 (GLUT-3) under hypoxic conditions selectively. The mRNA and protein expression of HIF-1α were also suppressed by TX-402 at the same time.Conclusion : The potent antiangiogenic effects of hypoxic cytotoxins can be attributed to the suppression of VEGF and HIF-1 induction through the hypoxia-inducible pathway. We show an other aspect of the hypoxic cytotoxin as an HIF-1 inhibitor for hypoxia-targeted therapy to improve cancer treatment and prognosis.

背景：缺氧是癌症治疗的重要肿瘤特异性靶标。我们已经报道了低氧细胞毒素，例如TX-1112，钛（TPZ）和TX-402，在低氧条件下选择性地诱导了肿瘤细胞对p53独立的凋亡，并抑制了血管生成。头颈部人类方形细胞癌（SAS细胞）和p53缺乏人类非小细胞肺癌H1299细胞用野生型或Mutantp53基因翻译的细胞毒性：TX-402具有更多潜在的潜在的低氧蛋白质细胞毒性。无论p53状态如何所有化合物在雏鸡胚胎绒毛膜膜（CAM）测定中可能以超过5μg/cam的剂量抑制血管生成。 RT-PCR分析表明，在低氧条件下，TX-402降低了血管内皮细胞生长因子（VEGE）和葡萄糖转运蛋白3（GLUT-3）的诱导表达。 TX-402同时也抑制了HIF-1α的mRNA和蛋白质表达。结论：低氧细胞毒素的潜在抗血管生成作用可以归因于通过低氧诱导途径抑制VEGF和HIF-1诱导。我们将低氧细胞毒素作为HIF-1抑制剂的另一个方面进行了低氧治疗，以改善癌症治疗和预后。