RRC ID 41736
Author Nakamura K, Sugumi H, Yamaguchi A, Uenaka T, Kotake Y, Okada T, Kamata J, Niijima J, Nagasu T, Koyanagi N, Yoshino H, Kitoh K, Yoshimatsu K.
Title Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor.
Journal Mol Cancer Ther
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.
Volume 1(3)
Pages 169-75
Published 2002-1-1
PMID 12467211
MeSH 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
IF 5.615
Times Cited 26
WOS Category ONCOLOGY
Resource
Human and Animal Cells HGC-27(RCB0500) GT3TKB(RCB0885)