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.

Abstract

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 beta-tubulin mutations were assayed in vitro and in murine xenografts.

RESULTS:

MST-997 induced microtubule polymerization (EC50 = 0.9 micromol/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 beta-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.

• Authors: Deepak Sampath, Lee M Greenberger, Carl Beyer, Malathi Hari, Hao Liu, Michelle Baxter, Sharon Yang, Carol Rios, Carolyn Discafani
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 11 Pt 1 Pg. 3459-69 (Jun 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16740771 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• MST 997
• Taxoids
• Tubulin
• Docetaxel
• Paclitaxel

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Binding Sites
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Docetaxel
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Female
• Humans
• In Situ Hybridization, Fluorescence
• Injections, Intravenous
• Mice
• Mice, Nude
• Molecular Conformation
• Paclitaxel (chemistry, pharmacology)
• Stereoisomerism
• Taxoids (administration & dosage, chemistry, pharmacology)
• Tubulin (drug effects)
• Xenograft Model Antitumor Assays