Therapeutic efficacy of a new topoisomerase I and II inhibitor TAS-103, against both P-glycoprotein-expressing and -nonexpressing drug-resistant human small-cell lung cancer

We examined the effect of a novel topoisomerase I and II (topo I and Il) in hibitor, TAS-103, on P-glycoprotein (P-gp)-expressing and -nonexpressing dr ug-resistant human small-cell lung cancer (SCLC) cells in vitro and in vivo . We observed that TAS-103 was effective in inhibiting in vitro proliferati on of human SCLC (SBC-3 and H69) cells and their drug-resistant variants SB C-3/ADM or SBC-3/CDDP and H-69/VP, respectively. SBC-3/ADM and H-69/VP expr essed high P-gp, whereas SBC-3/CDDP did not. TAS-103 also effectively reduc ed the tumor growth (more than 50% inhibition) of the parental as well as M DR SCLC cells grown SC in nude mice. Adriamycin (ADM) and cisplatin (CDDP), on the other hand, were effective only against the parental cells, while t hese drugs failed to inhibit the respective drug-resistant variants in vitr o or in vivo. TAS-103 was observed to induce apoptosis dose dependently in the parental as well as drug-resistant SCLC cells as analyzed after 48 h of in vitro treatment, suggesting that the stabilization of cleavable topo I- or II-DNA complexes by topo I and II inhibitors like TAS-103 is followed b y apoptosis of the cells. Overall, our study suggests that TAS-103 may have clinical application against drug-resistant human SCLC.