Department of Pathology and Bosch Institute, University of Sydney, Sydney, Australia.
Antioxid Redox Signal. 2013 Mar 10;18(8):973-1006. doi: 10.1089/ars.2012.4540. Epub 2012 May 11.
Under normal circumstances, cellular iron levels are tightly regulated due to the potential toxic effects of this metal ion. There is evidence that tumors possess altered iron homeostasis, which is mediated by the perturbed expression of iron-related proteins, for example, transferrin receptor 1, ferritin and ferroportin 1. The de-regulation of iron homeostasis in cancer cells reveals a particular vulnerability to iron-depletion using iron chelators. In this review, we examine the absorption of iron from the gut; its transport, metabolism, and homeostasis in mammals; and the molecular pathways involved. Additionally, evidence for alterations in iron processing in cancer are described along with the perturbations in other biologically important transition metal ions, for example, copper(II) and zinc(II). These changes can be therapeutically manipulated by the use of novel chelators that have recently been shown to be highly effective in terms of inhibiting tumor growth.
Such chelators include those of the thiosemicarbazone class that were originally thought to target only ribonucleotide reductase, but are now known to have multiple effects, including the generation of cytotoxic radicals.
Several chelators have shown marked anti-tumor activity in vivo against a variety of solid tumors. An important aspect is the toxicology and the efficacy of these agents in clinical trials.
As part of the process of the clinical assessment of the new chelators, an extensive toxicological assessment in multiple animal models is essential for designing appropriate dosing protocols in humans.
在正常情况下，由于这种金属离子的潜在毒性作用，细胞内的铁含量受到严格调节。有证据表明，肿瘤具有改变的铁稳态，这是通过铁相关蛋白表达的紊乱来介导的，例如转铁蛋白受体 1、铁蛋白和亚铁转运蛋白 1。癌细胞中铁稳态的失调揭示了使用铁螯合剂对铁耗竭的特殊易感性。在这篇综述中，我们检查了铁从肠道中的吸收；其在哺乳动物中的运输、代谢和稳态；以及涉及的分子途径。此外，还描述了癌症中铁处理的改变以及其他生物重要的过渡金属离子（例如铜（II）和锌（II））的紊乱。这些变化可以通过使用新型螯合剂来进行治疗性操纵，最近已经证明这些螯合剂在抑制肿瘤生长方面非常有效。
此类螯合剂包括最初被认为仅靶向核糖核苷酸还原酶的噻唑烷酮类，现在已知具有多种作用，包括产生细胞毒性自由基。
几种螯合剂在体内对多种实体瘤显示出明显的抗肿瘤活性。一个重要的方面是这些药物的毒理学和在临床试验中的疗效。
作为新螯合剂临床评估过程的一部分，在多种动物模型中进行广泛的毒理学评估对于设计人类适当的剂量方案至关重要。
