論文 - 詳細
| RRC ID | 41736 |
|---|---|
| 著者 | Nakamura K, Sugumi H, Yamaguchi A, Uenaka T, Kotake Y, Okada T, Kamata J, Niijima J, Nagasu T, Koyanagi N, Yoshino H, Kitoh K, Yoshimatsu K. |
| タイトル | Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor. |
| ジャーナル | Mol Cancer Ther |
| Abstract |
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. |
| 巻・号 | 1(3) |
| ページ | 169-75 |
| 公開日 | 2002-1-1 |
| PMID | 12467211 |
| MeSH | Amsacrine / pharmacology Animals Antineoplastic Agents / pharmacology* Carbazoles / pharmacology* Colonic Neoplasms / drug therapy* Colonic Neoplasms / enzymology Colonic Neoplasms / pathology Cross-Linking Reagents DNA, Neoplasm / drug effects Doxorubicin / pharmacology Drug Resistance, Neoplasm Enzyme Inhibitors / pharmacology* Etoposide / pharmacology Female Humans In Vitro Techniques Leukemia P388 / drug therapy Leukemia P388 / enzymology Leukemia P388 / pathology Mice Mice, Inbred C57BL Pyrimidines / pharmacology* Topoisomerase II Inhibitors* Tumor Cells, Cultured / drug effects Tumor Cells, Cultured / enzymology Tumor Cells, Cultured / pathology |
| IF | 5.615 |
| 引用数 | 26 |
| WOS 分野 | ONCOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HGC-27(RCB0500) GT3TKB(RCB0885) |