Doktorova Helena, Hrabeta Jan, Khalil Mohamed Ashraf, Eckschlager Tomas
Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015 Jun;159(2):166-77. doi: 10.5507/bp.2015.025. Epub 2015 May 19.
The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use.
Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results.
The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.
本综述旨在提供关于缺氧诱导化疗耐药分子基础的信息，重点关注其诊断和治疗应用的可能性。
缺氧是肿瘤的常见特征，也是许多癌症的独立预后因素。它是肿瘤中异常血管以及癌细胞快速增殖导致氧气摄入与消耗失衡的结果。多项实验报道了缺氧诱导对顺铂、阿霉素、依托泊苷、美法仑、5-氟尿嘧啶、吉西他滨和多西他赛的耐药性。肿瘤细胞对缺氧的适应具有重要生物学效应。对此效应研究最多的因素是缺氧诱导因子-1（HIF-1），它对不同肿瘤的侵袭性和化疗耐药性有显著影响。缺氧诱导的HIF-1复合物与靶基因结合，从而增加许多基因的表达。此外，数百个基因的表达也可通过依赖HIF-1的方式对缺氧作出反应而降低，但在这些基因的启动子中未检测到HIF-1。然而，缺氧时耐药的HIF-1非依赖机制已有描述，但仍很少报道。首批聚焦于缺氧诊断及抑制癌细胞中缺氧诱导变化的临床研究已开始取得成果。
对缺氧的适应需要许多相互调节的遗传和生化反应。缺氧诱导的耐药是一个非常复杂的领域，我们对此仍知之甚少。目前正在开发不同的方法来规避肿瘤中的缺氧情况。
