Rapisarda Annamaria, Zalek Jessica, Hollingshead Melinda, Braunschweig Till, Uranchimeg Badarch, Bonomi Carrie A, Borgel Suzanne D, Carter John P, Hewitt Stephen M, Shoemaker Robert H, Melillo Giovanni
Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
Cancer Res. 2004 Oct 1;64(19):6845-8. doi: 10.1158/0008-5472.CAN-04-2116.
We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1alpha protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1alpha protein expression in U251-HRE glioblastoma xenografts. Concomitant with HIF-1alpha inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissue. These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients.
我们之前已经表明，拓扑替康作为一种拓扑异构酶I抑制剂，通过一种不依赖DNA损伤的机制抑制缺氧诱导因子（HIF）-1α蛋白的积累。在此，我们报告每日给予拓扑替康可抑制U251-HRE胶质母细胞瘤异种移植瘤中HIF-1α蛋白的表达。与HIF-1α抑制相伴的是，拓扑替康导致肿瘤显著生长抑制，这与肿瘤组织中血管生成及HIF-1靶基因表达的显著降低相关。这些结果为在针对癌症患者HIF-1的临床试验中测试拓扑替康提供了令人信服的理论依据。
