Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison
Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison
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DOI：
10.1124/mol.104.003889
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发表时间：
2005-02-01
影响因子：
3.6
通讯作者：
Pommier, Y
中科院分区：
文献类型：
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作者：
Antony, S;Kohlhagen, G;Pommier, Y
为了克服喜树碱（CPT）内酯的不稳定性、药物-靶标相互作用的可逆性和耐药性，一直在尝试合成在其特异性和效力方面与CPT相似但显示出独特特征的化合物。在这一过程中，我们鉴定了一种异喹啉衍生物MJ-III-65（NSC 706744; 6-[3-（2-羟乙基）氨基-1-丙基]-5，6-二氢-2，3-二甲氧基-8，9-亚甲二氧基-5，11-二氧代-11H-茚并[1，2-c]异喹啉），它与CPT既有相似之处，也有不同之处。MJ-III- 65捕获拓扑异构酶I（Top1）可逆地像CPT，但具有不同的DNA序列偏好。与Top1中毒一致，在用纳摩尔浓度的MJ-III-65处理的细胞中检测到蛋白质连接的DNA断裂。这些MJ-III-65诱导的蛋白质连接的DNA断裂在药物去除一小时后抵抗逆转，而CPT完全逆转。对培养的人类细胞的研究发现MJ-III-65具有细胞毒性。此外，在喜树碱耐药细胞系中观察到有限的交叉耐药。MJ-III-65在小鼠肿瘤异种移植物中也表现出抗肿瘤活性。
To overcome camptothecin's (CPT) lactone instability, reversibility of the drug-target interaction, and drug resistance, attempts to synthesize compounds that are CPT-like in their specificity and potency yet display a unique profile have been underway. In this pursuit, we have identified one of the idenoisoquinoline derivatives, MJ-III-65 (NSC 706744; 6-[3-(2-hydroxyethyl)amino-1-propyl]-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline) with both similarities and differences from CPT. MJ-III- 65 traps topoisomerase I (Top1) reversibly like CPT but with different DNA sequence preferences. Consistent with Top1 poisoning, protein-linked DNA breaks were detected in cells treated with MJ-III-65 at nanomolar concentrations. These MJ-III-65-induced protein-linked DNA breaks were resistant to reversal after an hour of drug removal, compared with CPT, which completely reversed. Studies in human cells in culture found MJ-III-65 to be cytotoxic. Furthermore, limited cross-resistance was observed in camptothecin-resistant cell lines. MJ-III-65 also exhibits antitumor activity in mouse tumor xenografts.