Open AccessA novel carbazole topoisomerase II poison, ER‐37328: potent tumoricidal activity against human solid tumors in vitro and in vivo
Author(s) -
Nakamura Katsuji,
Uenaka Toshimitsu,
Nagasu Takeshi,
Sugumi Hiroyuki,
Yamaguchi Atsumi,
Kotake Yoshihiko,
Okada Toshimi,
Kamata Junichi,
Niijima Jun,
Taniguchi Tomoyoshi,
Koyanagi Nozomu,
Yoshino Hiroshi,
Kitoh Kyosuke,
Yoshimatsu Kentaro
Publication year - 2003
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2003.tb01362.x
Subject(s) - in vivo , in vitro , topoisomerase , pharmacology , solid tumor , cancer research , carbazole , chemistry , medicine , biology , cancer , biochemistry , microbiology and biotechnology , organic chemistry
We have discovered a novel topoisomerase II (topo II) poison, ER‐37328 (12,13‐dihydro‐5‐[2‐(dimethylamino)ethyl]‐4H‐benzo[c]py‐rimido[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 (LC 50 s) ranging from 2.9 to 20 μM ) than etoposide (LC 50 s>60 μM ) 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 μM . After removal of the drug (2.5 μM ) at 1 h, incubation was continued in drug‐free medium, and the amount of cleaved DNA decreased. However, at 10 μM , which is close to the LC 50 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 ER37328 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. (Cancer Sci 2003; 94: 119–124)