論文 - 詳細
| RRC ID | 61202 |
|---|---|
| 著者 | Nakamura K, Uenaka T, Nagasu T, Sugumi H, Yamaguchi A, Kotake Y, Okada T, Kamata J, Niijima J, Taniguchi T, Koyanagi N, Yoshino H, Kitoh K, Yoshimatsu K. |
| タイトル | A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo. |
| ジャーナル | Cancer Sci |
| Abstract |
We have discovered a novel topoisomerase II (topo II) poison, 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), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell-killing activity against a panel of human cancer cell lines and the antitumor activity of ER-37328 against human tumor xenografts. In a cell-killing assay involving 1-h drug treatment, ER-37328 showed more potent cell-killing activity (50% lethal concentrations (LC50s) ranging from 2.9 to 20 microM) than etoposide (LC50s>60 microM) against a panel of human cancer cell lines. ER-37328 induced double-stranded DNA cleavage, an indicator of topo II-DNA cleavable complex formation, within 1 h in MX-1 cells, and the extent of cleavage showed a bell-shaped relationship to drug concentration, with the maximum at 2.5 microM. After removal of the drug (2.5 microM) at 1 h, incubation was continued in drug-free medium, and the amount of cleaved DNA decreased. However, at 10 microM, which is close to the LC50s against MX-1 cells, DNA cleavage was not detected immediately after 1-h treatment, but appeared and increased after drug removal. This result may explain the potent cell-killing activity of ER-37328 in the 1-h treatment. In vivo, ER-37328 showed potent tumor regression activity against MX-1 and NS-3 tumors. Moreover, ER-37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER-37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo, and is a candidate for the clinical treatment of malignant solid tumors. |
| 巻・号 | 94(1) |
| ページ | 119-24 |
| 公開日 | 2003-1-1 |
| DOI | 10.1111/j.1349-7006.2003.tb01362.x |
| PMID | 12708485 |
| MeSH | Adenocarcinoma / pathology Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Apoptosis / drug effects Breast Neoplasms / pathology Carbazoles / pharmacology Carbazoles / therapeutic use* Colonic Neoplasms / pathology DNA Damage DNA, Neoplasm / analysis Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Enzyme Inhibitors / therapeutic use* Etoposide / therapeutic use Female Humans Lung Neoplasms / pathology Macromolecular Substances Mice Mice, Inbred BALB C Mice, Nude Neoplasm Proteins / antagonists & inhibitors* Protein Binding / drug effects Pyrimidines / pharmacology Pyrimidines / therapeutic use* Stomach Neoplasms / pathology Topoisomerase II Inhibitors* Tumor Cells, Cultured / drug effects Xenograft Model Antitumor Assays |
| IF | 4.966 |
| 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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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | HGC-27(RCB0500) GT3TKB(RCB0885) |