title: Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors.
abstract: OBJECTIVE
  Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.
  
  
  METHODS
  Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.
  
  
  RESULTS
  In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013-0.414 μmol/L; docetaxel, 0.17-4.01 μmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).
  
  
  CONCLUSIONS
  Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.
authors.affiliation: Sanofi, Vitry-sur-Seine, France. patricia.vrignaud@sanofi.com
authors.forename: Patricia
authors.initials: P
authors.lastname: Vrignaud
authors.forename: Dorothée
authors.initials: D
authors.lastname: Sémiond
authors.forename: Pascale
authors.initials: P
authors.lastname: Lejeune
authors.forename: Hervé
authors.initials: H
authors.lastname: Bouchard
authors.forename: Loreley
authors.initials: L
authors.lastname: Calvet
authors.forename: Cecile
authors.initials: C
authors.lastname: Combeau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Riou
authors.forename: Alain
authors.initials: A
authors.lastname: Commerçon
authors.forename: François
authors.initials: F
authors.lastname: Lavelle
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Bissery
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008868:Microtubule Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008868:Microtubule Proteins; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel