Molecular design of hypoxia-targeting anticancer drug.

背景：低氧是肿瘤治疗的一个重要靶点。我们研究了TX-1102、替拉帕明(TPZ)和TX-402等低氧细胞毒素在低氧条件下选择性诱导肿瘤细胞P53非依赖性凋亡并抑制血管生成。方法：研究抗血管生成低氧细胞毒素对人头颈部鳞状细胞癌(SAS细胞)和野生型和突变型P53基因缺陷人非小细胞肺癌H1299细胞缺氧诱导基因表达和低氧选择性细胞毒作用的影响。无论P53处于何种状态，在两种细胞中的表达均高于TPZ。在鸡胚绒毛膜尿囊膜实验中，所有化合物在5μg/cam以上剂量时均能有效地抑制血管生成。RT-PCR分析表明，TX-402选择性地抑制低氧条件下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。结论：低氧细胞毒素的抗血管生成作用可能与其通过低氧诱导途径抑制α和HIF-1的诱导有关。我们展示了低氧细胞毒素的另一个方面，作为一种HIF-1抑制剂，用于低氧靶向治疗，以改善癌症的治疗和预后。

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.