DNA: Still A Target Worth Aiming At?
DNA: Still A Target Worth Aiming At?
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DNA：仍然是一个值得瞄准的目标吗？
DOI：
--
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
C. Twelves
中科院分区：
文献类型：
--
作者：
D. Anthoney;C. Twelves
DNA是大多数临床有效的细胞毒剂的最终靶点，但缺乏对肿瘤细胞的选择性，这引发了人们对开发新的DNA相互作用药物的价值的质疑。综述了三类新的细胞毒剂；每一类都与DNA直接相互作用，但细胞毒性似乎是通过新的机制来介导的，包括通过DNA结合的药物分子与特定蛋白质的相互作用。它会引起一种新型的DNA损伤，其修复依赖于发挥作用的DNA解旋酶。已经观察到伊罗富芬和抑制拓扑异构酶的药物之间的临床前和临床协同作用。Irofulven的临床试验已经显示出显著的活性，胰腺癌、卵巢癌和前列腺癌的II期研究正在进行中。以骨髓抑制和疲劳的形式表现的毒性已被证明是依赖于时间表的，间歇给药似乎显著地减少了毒性。暴露在小沟中的烷化碱基的DNA相互作用剂来自许多自然来源。小沟槽的烷基化似乎是序列特异性的；尽管这种特异性对细胞毒性的意义尚不清楚，但一个被提出的机制是通过抑制特定基因的表达。三种引起序列特异性小槽烷基化的环丙基吡咯烷醇类似物目前正在接受临床评估。骨髓抑制是剂量限制性毒性，在其时间过程中是双相的。在第一阶段的试验中观察到了适度的活性。从海洋生物中分离出来的药物种类越来越多，其中之一就是环胞菌素。内毒素-743(ET-743)是临床研究中最先进的一种。与DNA的小凹槽结合发生，尽管与其他化合物具有不同的碱基专一性。ET-743的细胞毒作用可能是通过隔离特定转录因子而抑制一些基因的可诱导转录而发生的。ET-743的临床试验已经显示出显著的活性，软组织肉瘤和乳腺癌的II期试验正在进行中。肝脏毒性和骨髓抑制是可以预测的，似乎与血药浓度峰值有关，而疗效似乎随着时间的延长而提高。
DNA acts as the final target for most clinically effective cytotoxic agents, but the lack of selectivity for tumor cells has raised questions about the value of developing new DNA-interactive agents. Three new classes of cytotoxic agents are reviewed; each interacts directly with DNA but cytotoxicity appears to be mediated through novel mechanisms, including the interaction with specific proteins by DNA-bound drug molecules.Irofulven is the lead compound of the illudin family of molecules. It causes a novel type of DNA damage whose repair is dependent on functioning DNA helicases. Pre-clinical and clinical synergy between irofulven and agents which inhibit topoisomerases has been observed. Clinical trials with irofulven have shown significant activity and phase II studies in pancreatic, ovarian and prostatic cancer are ongoing. Toxicity in the form of myelosuppression and fatigue have been shown to be schedule dependent, with intermittent administration appearing to significantly reduce toxicity.DNA-interacting agents which alkylate bases exposed in the minor groove have been derived from a number of natural sources. The minor groove alkylation appears to be sequence specific; although the significance of this specificity for cytotoxicity is unclear, one proposed mechanism is through inhibition of expression of particular genes. Three cyclopropylpyrroloinole analogues which cause sequence specific minor groove alkylation are currently under clinical assessment. Myelosuppression is the dose limiting toxicity and is biphasic in its time course. Moderate activity in phase I trials has been observed.Ecteinascidins represent one of the increasing number of groups of drugs isolated from marine organisms. Ecteinascidin-743 (ET-743) is the most advanced in its clinical development. Binding to the minor groove of DNA occurs, although with a different base specificity from other compounds. The cytotoxic effects of ET-743 may occur by inhibition of the inducible transcription of a number of genes by sequestration of specific transcription factors. Clinical trials of ET-743 have shown significant activity, and phase II trials are underway in soft tissue sarcoma and breast cancer. Hepatic toxicity and myelosuppression are predictable and appear associated with peak plasma concentrations, whereas efficacy seems to be improved with prolonged infusion.
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DOI：
10.1073/pnas.97.12.6775
发表时间：
2000-06-06
影响因子：
11.1
作者：
Jin, S;Gorfajn, B;Scotto, KW
通讯作者：
Scotto, KW
隐伞素作为抗癌药物的临床前评价。
影响因子：
11.2
作者：
Kelner,MJ;McMorris,TC;Beck,WT;Zamora,JM;Taetle,R
通讯作者：
Taetle,R
DNA 链间交联、DNA 序列特异性以及 ( )-CC-1065 二聚体类似物产生的诱导构象变化。
DOI：
--
发表时间：
1991
期刊：
Anti-cancer drug design
影响因子：
--
作者：
Ding,ZM;Hurley,LH
通讯作者：
Hurley,LH
CC-1065 (NSC 298223) 与 DNA 相互作用的机制。
影响因子：
11.2
作者：
Swenson,DH;Li,LH;Hurley,LH;Rokem,JS;Petzold,GL;Dayton,BD;Wallace,TL;Lin,AH;Krueger,WC
通讯作者：
Krueger,WC