A novel carbazole topoisomerase II poison, ER‐37328: potent tumoricidal activity against human solid tumors in vitro and in vivo

• Published in: Cancer science 2003-01, Vol.94 (1), p.119-124
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms - pathology; Cancer; Carbazole; Carbazoles - pharmacology; Carbazoles - therapeutic use; Chemotherapy; Cisplatin; Colon; Colon cancer; Colonic Neoplasms - pathology; Deoxyribonucleic acid; DNA; DNA Damage; DNA topoisomerase (ATP-hydrolysing); DNA, Neoplasm - analysis; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Etoposide; Etoposide - therapeutic use; Female; Humans; Irinotecan; Lung Neoplasms - pathology; Macromolecular Substances; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - antagonists & inhibitors; Pharmacology. Drug treatments; Protein Binding - drug effects; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Solid tumors; Stomach Neoplasms - pathology; Topoisomerase II Inhibitors; Tumor cell lines; Tumor Cells, Cultured - drug effects; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2003.tb01362.x

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 (LC50s) ranging from 2.9 to 20 μM) than etoposide (LC50s>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 LC50 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)