Survivin, an apoptotic inhibitor, is overexpressed in the majority of human
tumor types and represents a novel target for anticancer
therapy.
Taxanes induce a mitotic cell-cycle block through the inhibition of microtubule depolymerization, with subsequent elevated expression/stabilization of
survivin. We investigated the administration of
survivin suppressant
YM155 monobromide (
YM155), in combination with
docetaxel, in a human
non-small-cell lung cancer (NSCLC) xenograft model. Animals received a 7-day continuous infusion of
YM155, 2 mg/kg, and/or three bolus doses of
docetaxel, 20 mg/kg, according to three dosing schedules:
YM155 administered concomitantly with
docetaxel, before
docetaxel, and after
docetaxel.
YM155 administered either concomitantly with or before
docetaxel showed significant antitumor activity (
tumor regression ≥ 99%), with complete regression of the established human NSCLC-derived
tumors in mice (eight of eight and seven of eight animals, respectively). Significantly fewer complete responses (three of eight animals) were achieved when
YM155 was administered after
docetaxel. No statistically significant decreases in
body weight were observed in the combination versus
docetaxel groups.
YM155 administered concomitantly with
docetaxel resulted in significant decreases in mitotic and proliferative indices, and in a significant increase in the apoptosis index. Elevated
survivin expression was seen in
tumors from mice treated with
docetaxel alone; a significant reduction in
survivin expression was seen in
tumors from mice treated with
YM155 alone or in combination with
docetaxel, but not in the control group. These results indicate that in a human NSCLC xenograft model
YM155 in combination with
docetaxel diminished the accumulation of
survivin by
docetaxel and induced more intense apoptosis and enhanced antitumor activity, compared with single-agent
YM155 or
docetaxel.