title: A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo.
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.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635. k2-nakamura@hhc.eisai.co.jp
authors.forename: Katsuji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugumi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kotake
authors.forename: Toshimi
authors.initials: T
authors.lastname: Okada
authors.forename: Junichi
authors.initials: J
authors.lastname: Kamata
authors.forename: Jun
authors.initials: J
authors.lastname: Niijima
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Nozomu
authors.initials: N
authors.lastname: Koyanagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kitoh
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimatsu
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000473:pathology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000473:pathology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004273:DNA, Neoplasm; C470233:ER37328; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors; D005047:Etoposide