Characterisation of a synergistic interaction between a thymidylate synthase inhibitor, ZD1694, and a novel lipophilic topoisomerase I inhibitor karenitecin, BNP1100: mechanisms and clinical implications.
Characterisation of a synergistic interaction between a thymidylate synthase inhibitor, ZD1694, and a novel lipophilic topoisomerase I inhibitor karenitecin, BNP1100: mechanisms and clinical implications.
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胸苷酸合成酶抑制剂 ZD1694 和新型亲脂性拓扑异构酶 I 抑制剂卡伦尼汀 BNP1100 之间协同相互作用的表征：机制和临床意义。
DOI：
10.1016/s0959-8049(99)00018-0
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发表时间：
1999
影响因子：
8.4
通讯作者：
Y. Rustum
中科院分区：
文献类型：
--
作者：
S. Matsui;W. Endo;C. Wrzosek;K. Haridas;P. Seetharamulu;Frederick H Hausheer;Y. Rustum
我们开发了一种胸苷酸合酶(TS)和DNA拓扑异构酶I(TOPO I)抑制剂的联合方案，该方案在体外对人结直肠癌细胞具有高度的杀伤力。构建了特定的程序，使得TS抑制剂不仅可以诱导初级DNA损伤，而且可以诱导最有利于Topo I抑制剂有效作用的细胞条件。最初的药物治疗包括短暂接触以喹唑啉为基础的抗叶酸ZD1694。在大约一个细胞倍增时间间隔后，细胞暴露于BNP1100，一种Karenitecin类7-硫甲基喜树碱，在1-10μM胸苷存在下；后者是一个关键因素，促进移动的复制叉与药物稳定的DNA-TOPO I可切割复合体的碰撞，即使在持续的TS抑制下。克隆形成分析证实，在临床可达到的浓度下，这些机制上不同的药物以高度协同的方式发挥作用，最大限度地消除了几乎所有癌细胞的活力(>；99.9%)。ZD1694的预处理使DNA结合的Topo I量增加了4倍，BNP1100的DNA损伤能力增加了15倍。提出了至少四条DNA损伤途径的可能性，这可能是TS和Topo I抑制剂单独作用以及它们协同作用的结果。综上所述，目前的发现提供了一个逻辑上允许的解释，为什么TS和Topo I抑制剂在协同作用中会产生高度致命的效应，而不是简单的相加效应。由于这些药物对活跃增殖的癌细胞有效，但对非周期的G0/G1细胞无效，这种基于机制的方案可能值得考虑用于临床验证。
We developed a combination protocol for inhibitors of thymidylate synthase (TS) and DNA topoisomerase I (Topo I) that can exert highly lethal effects in vitro against HCT-8 human colorectal cancer cells. The specific schedule was constructed so that a TS inhibitor could induce not only primary DNA damage but also cellular conditions optimal for the efficient action of a Topo I inhibitor. The initial drug treatment consisted of a brief exposure to a quinazoline-based antifolate, ZD1694. After an interval of approximately one cell-doubling time, cells were exposed for 8–24h to BNP1100, a Karenitecin-class 7-thiomethyl-camptothecin, in the presence of 1–10μM thymidine; the latter acted as a crucial factor to promote the collision of moving replication forks with the drug-stabilised DNA–Topo I cleavable complexes even under continuous TS inhibition. Clonogenic analyses confirmed that these mechanistically distinct drugs at clinically achievable concentrations worked in a highly synergistic manner, with a maximum effect abolishing the viability of virtually all cancer cells (>99.9%). The pretreatment with ZD1694 increased the amount of DNA-bound Topo I by up to 4-fold and the DNA-damaging capability of BNP1100 by up to 15-fold. The possibility of at least four DNA-damaging pathways is proposed which might have resulted from the individual actions of TS and Topo I inhibitors as well as their concerted actions. Taken together, the present findings provided a logically permissible explanation as to why TS and Topo I inhibitors in concerted interactions induced a highly lethal effect which was more than a simple additive effect. Since these drugs are effective specifically on actively proliferating cancer cells, but not on non-cycling G0/G1cells, this mechanism-based protocol may warrant consideration for clinical verification.
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DOI：
--
发表时间：
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期刊：
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影响因子：
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影响因子：
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作者：
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影响因子：
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DOI：
--
发表时间：
1996
期刊：
Cancer research.
影响因子：
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作者：
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