Trans-Platinum Complexes in Cancer Therapy
Trans-Platinum Complexes in Cancer Therapy
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DOI：
10.2174/187152007779314080
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发表时间：
2007-01-01
影响因子：
2.8
通讯作者：
Natile, Giovanni
中科院分区：
文献类型：
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作者：
Coluccia, Mauro;Natile, Giovanni
由于顺铂的反式异构体反式顺铂不起作用，目前对顺铂耐药/耐药的研究主要集中在顺式构型的化合物上。人们普遍认为反铂失活源于两个主要因素：1)促进其失活的动力学不稳定性；2)DNA加合物的形成，其特点是区域选择性和立体化学不同于顺铂。然而，已报道了一些例外情况，即顺式位置上两个离开基团的存在是铂配合物抗肿瘤活性所必需的。用芳香族N-供体杂环、支链脂肪胺或亚氨基配体取代反铂的氨基配体，可以得到体外抑制肿瘤细胞生长的化合物，通常对顺铂耐药/耐药的肿瘤细胞具有活性，在某些情况下，在体内也具有显著的活性。从机理上看，大体积配体取代氨基可以延缓两个氯配体的取代，从而降低反式铂化合物的动力学不稳定性。另一方面，DNA加合物的形成在性质和数量上都不同于顺铂，这有力地支持了抗肿瘤活性的反铂化合物可以具有不同的活性光谱的假设。人们希望，对反式铂化合物抗肿瘤活性背后的生化和细胞过程的了解不断增加，将促进其临床开发。
The research of new platinum drugs active towards cisplatin refractory/resistant tumors has been mostly focussed on compounds with cis geometry because transplatin, the trans-isomer of cisplatin, is inactive. It is widely accepted that transplatin inactivity stems from two major factors: i) the kinetic instability promoting its deactivation and ii) the formation of DNA adducts characterized by a regioselectivity and a stereochemistry different from those of cisplatin. However, several exceptions to the general rule that the presence of two leaving groups in cis positions is necessary for antitumor activity of platinum complexes, have been reported. Substitution of transplatin ammine ligands by aromatic N-donor heterocycles, branched aliphatic amines, or imino ligands has lead to compounds with relevant in vitro tumor cell growth inhibitory potency, often active towards cisplatin refractory/resistant tumor cells, and in some cases endowed with significant activity also in vivo. From a mechanistic point of view, substitution of bulky ligands for ammines can retard substitution of the two chloride ligands, thus reducing the kinetic instability of the trans-platinum compounds. On the other hand, the formation of DNA adducts qualitatively and quantitatively different from those of cisplatin strongly supports the hypothesis that antitumor-active trans-platinum complexes can have a different spectrum of activity. It is hoped that the increasing knowledge of the biochemical and cellular processes underlying the antitumor-activity of trans-platinum complexes will foster their clinical development.