Antitumor activity of a novel quinoline derivative, TAS-103, with inhibitory effects on topoisomerases I and II.

Abstract

A novel quinoline derivative, TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin -7-one dihydrochloride), was developed as an anticancer agent targeting topoisomerases (topo) I and II, with marked efficacy in solid tumors. TAS-103 inhibited topo I and II (IC50: 2 microM, 6.5 microM) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50: 0.0011 microM, 0.0096 microM). TAS-103 stabilized topo I and II-DNA cleavable complexes in KB cells, generating a similar amount of topo II-DNA complex to that induced by etoposide (VP-16) but a smaller amount of topo I-DNA complex than that produced by camptothecin (CPT). In the in vivo study, intermittent i.v. administration was markedly effective against s.c.-implanted murine tumors. Furthermore, TAS-103 had marked efficacy against various lung metastatic tumors, and a broad antitumor spectrum in human tumor xenografts (derived from lung, colon, stomach, breast, and pancreatic cancer). The efficacy of TAS-103 was generally greater than that of irinotecan (CPT-11), VP-16, or cis-diamminedichloroplatinum (CDDP).

• Authors: T Utsugi, K Aoyagi, T Asao, S Okazaki, Y Aoyagi, M Sano, K Wierzba, Y Yamada
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 88 Issue 10 Pg. 992-1002 (Oct 1997) ISSN: 0910-5050 [Print] Japan
• PMID: 9414662 (Publication Type: Journal Article)

Chemical References

• Aminoquinolines
• Antineoplastic Agents
• Indenes
• Indoles
• Pyridines
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Etoposide
• Irinotecan
• DNA
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II
• intoplicine
• Cisplatin
• Camptothecin
• 6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one

Topics

• Adenocarcinoma (prevention & control)
• Aminoquinolines (administration & dosage, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Camptothecin (analogs & derivatives, pharmacology)
• Cisplatin (pharmacology)
• Colonic Neoplasms (prevention & control)
• DNA (metabolism)
• DNA Topoisomerases, Type I (metabolism)
• DNA Topoisomerases, Type II (metabolism)
• Dose-Response Relationship, Drug
• Etoposide (pharmacology)
• Humans
• Indenes (administration & dosage, pharmacology, therapeutic use)
• Indoles (pharmacology)
• Irinotecan
• Lung Neoplasms (prevention & control)
• Male
• Melanoma (prevention & control)
• Mice
• Mice, Inbred Strains
• Neoplasm Transplantation
• Neoplasms, Experimental (prevention & control)
• Pyridines (pharmacology)
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured