Lani
06-27-2006, 02:18 PM
Clinical Cancer Research Vol. 12, 3459-3469, June 1, 2006
© 2006 American Association for Cancer Research
Cancer Therapy: Preclinical
Preclinical Pharmacologic Evaluation of MST-997, an Orally Active Taxane with Superior In vitro and In vivo Efficacy in Paclitaxel- and Docetaxel-Resistant Tumor Models
Deepak Sampath, Lee M. Greenberger, Carl Beyer, Malathi Hari, Hao Liu, Michelle Baxter, Sharon Yang, Carol Rios and Carolyn Discafani
Authors' Affiliation: Department of Oncology, Wyeth Research, Pearl River, New York
Requests for reprints: Deepak Sampath, Department of Translational Oncology, Genetech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-7786; Fax: 650-225-5770; E-mail: sampath.deepak@gene.com.
Purpose: Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought. The aim of this study was to evaluate the efficacy and oral activity of a novel taxane (MST-997) in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo.
Experimental Design: Tubulin polymerization assays, immunohistochemistry, and cell cycle analysis was used to evaluate mechanism of action of MST-997. The effect of MST-997 on growth inhibition in a panel of paclitaxel- and docetaxel-resistant cell lines that overexpressed P-glycoprotein (MDR1) or harbored ß-tubulin mutations were assayed in vitro and in murine xenografts.
Results: MST-997 induced microtubule polymerization (EC50 = 0.9 µmol/L) and bundling, resulting in G2-M arrest and apoptosis. In addition, MST-997 was a potent inhibitor of paclitaxel- and docetaxel-sensitive tumor cell lines that did not have detectable P-glycoprotein (IC50 = 1.8 ± 1.5 nmol/L). Minimal resistance (1- to 8-fold) to MST-997 was found in cell lines that either overexpressed MDR1 or harbored point mutations in ß-tubulin. Most notable, MST-997 displayed superior in vivo efficacy as a single i.v. or p.o. dose either partially or completely inhibited tumor growth in paclitaxel- and docetaxel-resistant xenografts.
Conclusions: MST-997 represents a potent and orally active microtubule-stabilizing agent that has greater pharmacologic efficacy in vitro and in vivo than the currently approved taxanes. Our findings suggest that MST-997, which has entered phase I clinical trials, may have broad therapeutic value.
© 2006 American Association for Cancer Research
Cancer Therapy: Preclinical
Preclinical Pharmacologic Evaluation of MST-997, an Orally Active Taxane with Superior In vitro and In vivo Efficacy in Paclitaxel- and Docetaxel-Resistant Tumor Models
Deepak Sampath, Lee M. Greenberger, Carl Beyer, Malathi Hari, Hao Liu, Michelle Baxter, Sharon Yang, Carol Rios and Carolyn Discafani
Authors' Affiliation: Department of Oncology, Wyeth Research, Pearl River, New York
Requests for reprints: Deepak Sampath, Department of Translational Oncology, Genetech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-7786; Fax: 650-225-5770; E-mail: sampath.deepak@gene.com.
Purpose: Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought. The aim of this study was to evaluate the efficacy and oral activity of a novel taxane (MST-997) in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo.
Experimental Design: Tubulin polymerization assays, immunohistochemistry, and cell cycle analysis was used to evaluate mechanism of action of MST-997. The effect of MST-997 on growth inhibition in a panel of paclitaxel- and docetaxel-resistant cell lines that overexpressed P-glycoprotein (MDR1) or harbored ß-tubulin mutations were assayed in vitro and in murine xenografts.
Results: MST-997 induced microtubule polymerization (EC50 = 0.9 µmol/L) and bundling, resulting in G2-M arrest and apoptosis. In addition, MST-997 was a potent inhibitor of paclitaxel- and docetaxel-sensitive tumor cell lines that did not have detectable P-glycoprotein (IC50 = 1.8 ± 1.5 nmol/L). Minimal resistance (1- to 8-fold) to MST-997 was found in cell lines that either overexpressed MDR1 or harbored point mutations in ß-tubulin. Most notable, MST-997 displayed superior in vivo efficacy as a single i.v. or p.o. dose either partially or completely inhibited tumor growth in paclitaxel- and docetaxel-resistant xenografts.
Conclusions: MST-997 represents a potent and orally active microtubule-stabilizing agent that has greater pharmacologic efficacy in vitro and in vivo than the currently approved taxanes. Our findings suggest that MST-997, which has entered phase I clinical trials, may have broad therapeutic value.