Kicic Anthony, Chua Anita C G, Baker Erica
Department of Physiology, University of Western Australia, Nedlands 6907, Western Australia, Australia.
Br J Pharmacol. 2002 Mar;135(6):1393-402. doi: 10.1038/sj.bjp.0704507.
Desferrithiocin (DFT) is an orally effective Fe chelator, with a similar high affinity and selectivity for Fe to desferrioxamine (DFO), which has been shown clinically to possess antineoplastic activity. In this study, DFT was assessed for antineoplastic potential in hepatocellular carcinoma cell lines (HCC). This was done as there are few treatments for this aggressive neoplasm. The effects of DFT on cell proliferation, cell cycle progression, Fe uptake and toxicity were examined. To establish whether DFT was selective for cancer cells a comparison was made with normal (non-proliferating) hepatocytes and non-tumorigenic (proliferating) fibroblasts (SWISS-3T3). DFT was a potent inhibitor of HCC proliferation (IC(50) approximately 40 microM). DFO also inhibited HCC proliferation under the same conditions, but was much less active (IC(50)=110 - 210 microM). When saturated with Fe, the activity of DFT, like DFO, was greatly diminished, suggesting it may act by depriving the cells of Fe or inactivating essential Fe pool(s). Indeed DFT rapidly decreased Fe uptake from Tf-(59)Fe by hepatoma cells and also by normal hepatocytes. However, DFT (and DFO) had much less effect on cell survival in hepatocytes and fibroblasts than in hepatoma cells. DFT may, like DFO, inhibit the cell cycle in the S phase of DNA synthesis. Both chelators showed low toxicity. These results indicate that DFT has potent antineoplastic activity in HCC. Further investigation into the DFT class of Fe chelators seems warranted, particularly in view of its high activity in relation to DFO, a chelator which is already in clinical trial for neuroblastoma.
去铁硫菌素（DFT）是一种口服有效的铁螯合剂，对铁具有与去铁胺（DFO）相似的高亲和力和选择性，临床研究表明其具有抗肿瘤活性。在本研究中，对DFT在肝癌细胞系（HCC）中的抗肿瘤潜力进行了评估。之所以这样做，是因为针对这种侵袭性肿瘤的治疗方法很少。研究了DFT对细胞增殖、细胞周期进程、铁摄取和毒性的影响。为确定DFT是否对癌细胞具有选择性，将其与正常（非增殖）肝细胞和非致瘤性（增殖）成纤维细胞（SWISS - 3T3）进行了比较。DFT是HCC增殖的有效抑制剂（半数抑制浓度（IC50）约为40微摩尔）。在相同条件下，DFO也抑制HCC增殖，但活性低得多（IC50 = 110 - 210微摩尔）。当与铁饱和时，DFT的活性与DFO一样会大大降低，这表明它可能通过剥夺细胞内的铁或使必需的铁池失活来发挥作用。事实上，DFT能迅速降低肝癌细胞以及正常肝细胞从转铁蛋白 - （59）铁摄取铁的量。然而，DFT（和DFO）对肝细胞和成纤维细胞存活的影响比对肝癌细胞的影响小得多。DFT可能与DFO一样，在DNA合成的S期抑制细胞周期。两种螯合剂均显示出低毒性。这些结果表明DFT在HCC中具有强大的抗肿瘤活性。鉴于其相对于DFO具有高活性，而DFO已在进行神经母细胞瘤的临床试验，因此对DFT类铁螯合剂进行进一步研究似乎是有必要的。
