title: 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.affiliation: Taiho Pharmaceutical Co. Ltd., Hanno Research Center, Saitama.
authors.forename: T
authors.initials: T
authors.lastname: Utsugi
authors.forename: K
authors.initials: K
authors.lastname: Aoyagi
authors.forename: T
authors.initials: T
authors.lastname: Asao
authors.forename: S
authors.initials: S
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Aoyagi
authors.forename: M
authors.initials: M
authors.lastname: Sano
authors.forename: K
authors.initials: K
authors.lastname: Wierzba
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000230:Adenocarcinoma / Q000517:prevention & control; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000517:prevention & control; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007192:Indenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000517:prevention & control; D008297:Male; D008545:Melanoma / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D007192:Indenes; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C081834:intoplicine; D002945:Cisplatin; D002166:Camptothecin; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one