Open AccessAntitumor Activity of a Novel Quinoline Derivative, TAS‐103, with Inhibitory Effects on Topoisomerases I and II
Author(s) -
Utsugi Teruhiro,
Aoyagi Kumio,
Asao Tetsuji,
Okazaki Shinji,
Aoyagi Yoshimi,
Sano Masaki,
Wierzba Konstanty,
Yamada Yuji
Publication year - 1997
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1997.tb00320.x
Subject(s) - topoisomerase , etoposide , camptothecin , irinotecan , in vivo , pharmacology , quinoline , ic50 , chemistry , topoisomerase inhibitor , biology , cancer research , in vitro , stereochemistry , chemotherapy , cancer , biochemistry , colorectal cancer , microbiology and biotechnology , organic chemistry , genetics
A novel quinoline derivative, TAS‐103 (6‐[[2‐(dimethyIamino)ethyl]amino]‐3‐hydroxy‐7 H ‐indeno[2,l‐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 (IC 50 : 2 μM, 6.5 μM ) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC 50 ,: 0.0011 μM, 0.0096 μM ). 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).