Preclinical efficacy spectrum and pharmacokinetics of ixabepilone |
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Authors: | Francis Y F Lee Richard Smykla Kathy Johnston Krista Menard Kelly McGlinchey Russell W Peterson Amy Wiebesiek Gregory Vite Craig R Fairchild Robert Kramer |
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Institution: | (1) Oncology Drug Discovery, Bristol–Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, K22-03, Princeton, NJ 08540, USA |
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Abstract: | Purpose Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends
previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes
the pharmacokinetics of this new antineoplastic agent.
Methods The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts
in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential
drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The
pharmacokinetic profile of ixabepilone was established in mice and humans.
Results Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts
in vivo. Ixabepilone was ~3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant
due to overexpression of βIII-tubulin and a lack of βII-tubulin). Ixabepilone activity against P-gp-overexpressing breast
and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a
P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive
tissue binding.
Conclusions Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum
antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance
due to P-gp overexpression, tubulin mutations, and alterations in β-tubulin isotype expression. |
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Keywords: | Ixabepilone Antineoplastic Pharmacokinetics Drug resistance P-glycoprotein Taxane Tubulin Breast cancer Epothilone |
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