Nakamura Katsuji, Sugumi Hiroyuki, Yamaguchi Atsumi, Uenaka Toshimitsu, Kotake Yoshihiko, Okada Toshimi, Kamata Junichi, Niijima Jun, Nagasu Takeshi, Koyanagi Nozomu, Yoshino Hiroshi, Kitoh Kyosuke, Yoshimatsu Kentaro
Discovery Research Laboratories II (Oncology), Tsukuba Research Laboratories, Eisai Co. Ltd., 1-3 Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2635, Japan.
Mol Cancer Ther. 2002 Jan;1(3):169-75.
DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)-trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and (b) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo.
DNA拓扑异构酶II已被证明是癌症化疗中的一个重要治疗靶点。在此，我们描述了一种新型拓扑异构酶II抑制剂ER-37328 [12,13-二氢-5-[2-(二甲基氨基)乙基]-4H-苯并[c]嘧啶并[5,6,1-jk]咔唑-4,6,10(5H,11H)-三酮盐酸盐]的抗肿瘤活性研究。在松弛试验中，ER-37328抑制拓扑异构酶II活性的浓度比依托泊苷低10倍，并在1小时内诱导小鼠白血病P388细胞中的双链DNA断裂，其断裂量与药物浓度呈钟形关系。在2 microM时获得最大DNA断裂量。与依托泊苷一样，ER-37328（2 microM）在P388细胞中诱导拓扑异构酶II-DNA交联。对ER-37328与DNA混合物的光谱研究表明，ER-37328对DNA具有明显的结合活性。ER-37328对一组21种人类癌细胞系显示出强大的生长抑制活性[平均（50%生长抑制浓度）GI50 = 59 nM]。根据美国国立癌症研究所筛选方案进行的COMPARE分析表明，ER-37328的生长抑制作用模式与依托泊苷相似，但与多柔比星不同。对依托泊苷、安吖啶[4'-(9-吖啶基氨基)甲磺酰基间甲氧基苯胺（m-AMSA）]和喜树碱耐药的P388细胞系的研究表明：（a）与亲代细胞系相比，依托泊苷和m-AMSA耐药的P388细胞系对ER-37328有部分耐药性；（b）喜树碱耐药细胞系对ER-37328无交叉耐药性。此外，ER-37328克服了P-糖蛋白介导的耐药性。在体内，ER-37328对皮下接种的结肠癌38癌产生了强大的肿瘤消退作用，其活性优于依托泊苷或多柔比星。这些结果表明，ER-37328通过形成拓扑异构酶II-DNA可裂解复合物来抑制拓扑异构酶II活性，并且在体外和体内均具有强大的抗肿瘤活性。
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