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DJ‐927, a novel oral taxane, overcomes P‐glycoprotein‐mediated multidrug resistance in vitro and in vivo

DJ‐927 is a novel taxane, which was selected for high solubility, non‐neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ‐927 with those of paclitaxel and docetaxel. DJ‐927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P‐glycoprotein (P‐gp)‐expressing cells. The cytotoxicity of DJ‐927, unlike those of other taxanes, was not affected by the P‐gp expression level in tumor cells, or by the co‐presence of a P‐gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ‐927 were much higher than those of paclitaxel or docetaxel, particularly in P‐gp‐positive cells. In vivo, DJ‐927 showed potent antitumor effects against two human solid tumors in male BALB/c‐nu/nu mice, and yielded significant life‐prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ‐927 over intravenously administered paclitaxel or docetaxel against P‐gp‐expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ‐927 is currently ongoing in the US. (Cancer Sci 2003; 94: 459–466)