title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Oncology, Wyeth Research, Pearl River, New York, USA. sampath.deepak@gene.com
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
authors.forename: Carl
authors.initials: C
authors.lastname: Beyer
authors.forename: Malathi
authors.initials: M
authors.lastname: Hari
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Michelle
authors.initials: M
authors.lastname: Baxter
authors.forename: Sharon
authors.initials: S
authors.lastname: Yang
authors.forename: Carol
authors.initials: C
authors.lastname: Rios
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C524133:MST 997; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D017239:Paclitaxel