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

铁（Fe）对增殖至关重要。通常，癌细胞具有高的Fe需求，这是由于它们的快速增殖速率使得它们对消耗细胞Fe的铁螯合剂非常敏感。这种疗法的潜力已经通过螯合剂Trillium（Vion Pharmaceuticals）进入临床试验得到证实。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）可以具有强效的抗肿瘤活性。实际上，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降低，同时没有显著的副作用，证明了可观的治疗指数。然而，DFO存在严重的问题，包括它需要长时间输注并且不容易渗透细胞。考虑到这一点，在目前的NHMRC资助期间，我们开发了一组新的螯合剂，其在体外和体内抑制癌症生长方面显示出比DFO和Trilidine大得多的活性（Richardson BLOOD 2004;104：1450）。这些研究已经发表在高质量的期刊上，例如BLOOD和Clin Cancer Res（Richardson 1995，1997，1999，2001，2002，2004 a，B，c）。最近，已经鉴定了一种有效的转移抑制基因，称为分化相关基因-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，我们最近已经表明，我们的新螯合剂显著上调癌细胞中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）。我们的假设是在用螯合剂处理后Drg-1表达的显著增加可以抑制癌细胞的生长和转移。在这个NHMRC资助更新的研究将导致新疗法的开发和癌症转移和生物学的更好的理解。

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.