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: Katsuji Nakamura, Hiroyuki Sugumi, Atsumi Yamaguchi, Toshimitsu Uenaka, Yoshihiko Kotake, Toshimi Okada, Junichi Kamata, Jun Niijima, Takeshi Nagasu, Nozomu Koyanagi, Hiroshi Yoshino, Kyosuke Kitoh, Kentaro Yoshimatsu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 3 Pg. 169-75 (Jan 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12467211 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Carbazoles
• Cross-Linking Reagents
• DNA, Neoplasm
• ER37328
• Enzyme Inhibitors
• Pyrimidines
• Topoisomerase II Inhibitors
• Amsacrine
• Etoposide
• Doxorubicin

Topics

• Amsacrine (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carbazoles (pharmacology)
• Colonic Neoplasms (drug therapy, enzymology, 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, enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Pyrimidines (pharmacology)
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured (drug effects, enzymology, pathology)