title: Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor.
abstract: 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 microM. Like etoposide, ER-37328 (2 microM) 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) GI50 = 59 nM]. 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.
authors.affiliation: Discovery Research Laboratories II (Oncology), Tsukuba Research Laboratories, Eisai Co. Ltd., 1-3 Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2635, Japan. k2-nakamura@hhc.eisai.co.jp
authors.forename: Katsuji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugumi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
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: Takeshi
authors.initials: T
authors.lastname: Nagasu
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: D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; C470233:ER37328; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D005047:Etoposide; D004317:Doxorubicin