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In Vivo Topoisomerase I Inhibition Attenuates the Expression of Hypoxia-Inducible Factor 1α Target Genes and Decreases Tumor Angiogenesis

机译:体内拓扑异构酶I抑制减弱缺氧诱导因子1α靶基因的表达并降低肿瘤血管生成。

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摘要

Topoisomerase I is a privileged target for widely used anticancer agents such as irinotecan. Although these drugs are classically considered to be DNA-damaging agents, increasing evidence suggests that they might also influence the tumor environment. This study evaluates in vivo cellular and molecular modifications induced by irinotecan, a topoisomerase I–directed agent, in patient-derived colon tumors subcutaneously implanted in athymic nude mice. Irinotecan was given intraperitoneally at 40 mg/kg five times every 5 d, and expression profiles were evaluated at d 25 in tumors from treated and untreated animals. Unexpectedly, the in vivo antitumor activity of irinotecan was closely linked to a downregulation of hypoxia-inducible factor-1α (HIF1A) target genes along with an inhibition of HIF1A protein accumulation. The consequence was a decrease in tumor angiogenesis leading to tumor size stabilization. These results highlight the molecular basis for the antitumor activity of a widely used anticancer agent, and the method used opens the way for mechanistic studies of the in vivo activity of other anticancer therapies.
机译:拓扑异构酶I是广泛使用的抗癌药(如伊立替康)的优先目标。尽管这些药物通常被认为是破坏DNA的药物,但越来越多的证据表明它们也可能影响肿瘤环境。这项研究评估了伊立替康(一种拓扑异构酶I导向剂)在无胸腺裸鼠皮下植入的患者来源的结肠肿瘤中诱导的体内细胞和分子修饰。每5 d腹膜内给予伊立替康40 mg / kg五次,并在d 25评估来自治疗和未治疗动物的肿瘤中的表达情况。出乎意料的是,伊立替康的体内抗肿瘤活性与低氧诱导因子-1α(HIF1A)靶基因的下调以及对HIF1A蛋白积累的抑制密切相关。结果是肿瘤血管生成减少,导致肿瘤大小稳定。这些结果突出了广泛使用的抗癌剂的抗肿瘤活性的分子基础,并且所使用的方法为其他抗癌疗法的体内活性的机理研究开辟了道路。

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