In vitro Antitumor Activity of TAS‐103, a Novel Quinoline Derivative That Targets Topoisomerases I and II

TAS‐103 is a novel anticancer agent targeting both topoisomerase (Topo) I and Topo II, that stabilizes cleavable complexes of Topo‐DNA at the cellular level. In this study, the in vitro antitumor effects of TAS‐103 were compared with those of other known Topo I and Topo II inhibitors. TAS‐103 inhibited DNA synthesis more strongly than RNA and protein synthesis, and induced an increase of cell population in the S‐G2/M phase. The cytotoxicity of TAS‐103 was strongest against S‐phase cells, but its cell cycle phase specificity was not clear, and depended on drug concentration and exposure time. The cytotoxicity of TAS‐103 (IC(50): 0.0030–0.23 μM) against various tumor cell lines was much stronger than that of VP‐16 and comparable to that of SN‐38. The cytotoxicity of TAS‐103 seemed to be more related to the amount of protein‐DNA complexes than to the accumulation of TAS‐103 in the cells. P‐Glycoprotein (P‐gp)‐mediated MDR, CDDP‐resistant and 5‐FU‐resistant cell lines did not show cross‐resistance to TAS‐103. Although PC‐7/CPT cells bearing a Topo I gene mutation showed cross‐resistance to TAS‐103, the sensitivity of P388/CPT, HT‐29/ CPT and St‐4/CPT cells, showing decreased Topo I expression, was not changed. KB/VM4 and HT‐29/Etp cells, showing decreased Topo II expression, were slightly cross‐resistant to TAS‐103. These results suggest that TAS‐103 may act as an inhibitor of both Topo I and Topo II at the cellular level. This property may be responsible for its strong antitumor effect and broad‐spectrum, growth‐inhibitory effect on drug‐resistant cell lines.