Antitumor Activity of ER-37328, a Novel Carbazole Topoisomerase II Inhibitor

• Published in: Molecular cancer therapeutics 2002-01, Vol.1 (3), p.169-175
• Main Authors: Nakamura, Katsuji, Sugumi, Hiroyuki, Yamaguchi, Atsumi, Uenaka, Toshimitsu, Kotake, Yoshihiko, Okada, Toshimi, Kamata, Junichi, Niijima, Jun, Nagasu, Takeshi, Koyanagi, Nozomu, Yoshino, Hiroshi, Kitoh, Kyosuke, Yoshimatsu, Kentaro
• Format: Article
• Language: English
• Subjects: Amsacrine - pharmacology; Animals; Antineoplastic Agents - pharmacology; Carbazoles - pharmacology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Cross-Linking Reagents; DNA, Neoplasm - drug effects; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Enzyme Inhibitors - pharmacology; Etoposide - pharmacology; Female; Humans; In Vitro Techniques; Leukemia P388 - drug therapy; Leukemia P388 - enzymology; Leukemia P388 - pathology; Mice; Mice, Inbred C57BL; Pyrimidines - pharmacology; Topoisomerase II Inhibitors; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - enzymology; Tumor Cells, Cultured - pathology
• ISSN: 1535-7163; 1538-8514

DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, 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]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 μ m . Like etoposide, ER-37328 (2 μ m ) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI 50 = 59 n m ]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: ( a ) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and ( b ) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo , ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo .