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

Abstract

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.

• Authors: Motoko Shionoya, Takeshi Jimbo, Mayumi Kitagawa, Tsunehiko Soga, Akiko Tohgo
• Journal: Cancer science (Cancer Sci) Vol. 94 Issue 5 Pg. 459-66 (May 2003) ISSN: 1347-9032 [Print] England
• PMID: 12824894 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Taxoids
• Docetaxel
• Paclitaxel
• tesetaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Survival (drug effects)
• Colony-Forming Units Assay
• Docetaxel
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasms, Experimental (drug therapy, metabolism)
• Paclitaxel (therapeutic use)
• Taxoids (therapeutic use)
• Tumor Cells, Cultured (drug effects, transplantation)