title: Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents.
abstract: OBJECTIVE
  The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared.
  
  
  METHODS
  Mouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts.
  
  
  RESULTS
  The IC(90) concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC(90)s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect.
  
  
  CONCLUSIONS
  Bringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
authors.affiliation: Genzyme Corporation, Framingham, MA 01701, USA. Leslie.Kurtzberg@Genzyme.com
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kurtzberg
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Roth
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Bagley
authors.forename: Cecile
authors.initials: C
authors.lastname: Rouleau
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Crawford
authors.forename: Roy D
authors.initials: RD
authors.lastname: Krumbholz
authors.forename: Steven M
authors.initials: SM
authors.lastname: Schmid
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Teicher
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D014404:Tubulin / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; D014404:Tubulin; C504233:tasidotin; D014750:Vincristine; D017239:Paclitaxel