RRC ID 61202
Author 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.
Title A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo.
Journal 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.
Volume 94(1)
Pages 119-24
Published 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
Human and Animal Cells HGC-27(RCB0500) GT3TKB(RCB0885)