Potential anti-tumour agents: Iron chelators of the pyridoxal isonicotinoyl hydrazone class

铁（Fe）是增殖所必需的。一般来说，癌细胞有很高的铁需求，因为它们的增殖速度很快，使它们非常容易受到铁螯合剂的影响，铁螯合剂会耗尽细胞中的铁。螯合剂Triapine （Vion Pharmaceuticals）进入临床试验，证实了这种疗法的潜力。此外，包括临床试验在内的各种研究表明，临床使用的铁螯合剂去铁胺（DFO）具有强大的抗肿瘤活性。事实上，在一项重要的临床试验中（Cancer Res 1990;50:4929），观察到肿瘤负荷显著减少，同时没有明显的副作用，显示出可观的治疗指数。然而，DFO存在严重的问题，包括需要长时间的注射，并且不易渗透细胞。考虑到这一点，在目前的NHMRC资助期间，我们开发了一组新型螯合剂，在体外和体内抑制癌症生长方面，它们的活性远高于DFO和Triapine （Richardson BLOOD 2004;104:1450）。这些研究已经发表在诸如BLOOD and clinicalcancer Res （Richardson 1995,1997,1999,2001,2002,2004a,b,c）等高质量期刊上。最近，一种有效的转移抑制基因被发现，称为分化相关基因-1 （differentiation related gene-1, Drg-1）。该分子的上调在抑制原发性癌症的生长及其转移性扩散中起重要作用。重要的是，我们最近的研究表明，我们的新螯合剂可以显著上调肿瘤细胞中Drg-1的表达，同时显著和选择性地抑制这些细胞的生长（Richardson BLOOD 2004;104:2967）。我们的假设是，螯合剂治疗后Drg-1表达的显著增加可以抑制癌细胞的生长和转移。这项NHMRC拨款更新的研究将导致新疗法的发展和对癌症转移和生物学的更好理解。

Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial (Cancer Res 1990;50:4929), a marked decrease in tumour burden was observed while there was no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers serious problems, including that it requires long infusions and does not readily permeate cells. Considering this, during the current NHMRC grant, we developed a novel group of chelators that show far greater activity than DFO and Triapine at inhibiting cancer growth in vitro and in vivo (Richardson BLOOD 2004;104:1450). These studies have been published in high quality journals such as BLOOD and Clin Cancer Res (Richardson 1995, 1997, 1999, 2001, 2002, 2004a,b,c) Recently, a potent metastasis suppressor gene, known as differentiation related gene-1 (Drg-1), has been identified. Up-regulation of this molecule plays an important role in inhibiting the growth of primary cancers and their metastatic spread. Importantly, we have recently shown that our new chelators markedly up-regulate the expression of Drg-1 in cancer cells and at the same time markedly and selectively inhibit the growth of these cells (Richardson BLOOD 2004;104:2967). Our hypothesis is the marked increase in Drg-1 expression after treatment with chelators could inhibit cancer cell growth and metastasis. Studies in this NHMRC grant renewal will lead to the development of new therapies and a greater understanding of cancer metastasis and biology.