ANTITUMOR-ACTIVITY OF A NOVEL QUINOLINE DERIVATIVE, TAS-103, WITH INHIBITORY EFFECTS ON TOPOISOMERASE-I AND TOPOISOMERASE-II

A novel quinoline derivative, TAS-103 (6-[[2-(dimethylamino) ethyl] am ino]-3-hydroxy-7H-indeno[2, 1-c]quinolin-7-one dihydrochloride), was d eveloped 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 mu M, 6.5 mu M) at a concentration similar to or lower th an those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50: 0.0011 mu M, 0.0096 mu M). TAS-103 Stabilized top o I and II-DNA cleavable complexes in KB cells, generating a similar a mount 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 camptothe cin (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, an d a broad antitumor spectrum in human tumor xenografts (derived from l ung, colon, stomach, breast, and pancreatic cancer). The efficacy of T AS-108 was generally greater than that of um (CDDP). irinotecan (CPT-1 1), VP-16, or cis-diamminedichloroplatinum (CDDP).