title: Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells.
abstract: BACKGROUND
  Paclitaxel is used widely in the treatment of breast cancer. Not all tumors respond to this drug, however, and the characteristics that distinguish resistant tumors from sensitive tumors are not well defined. Activation of the spindle assembly checkpoint is required for paclitaxel-induced cell death. We hypothesized that cyclin-dependent kinase (CDK) 1 activity and CDK2 activity in cancer cells, which reflect the activation state of the spindle assembly checkpoint and the growth state, respectively, predict sensitivity to paclitaxel.
  
  
  METHODS
  Cell viability assays and DNA and chromatin morphology analyses were performed in human breast cancer cell lines to evaluate sensitivity to paclitaxel and the cell cycle response to paclitaxel. We then examined the specific activities of CDK1 and CDK2 in these cell lines and in xenograft models of human breast cancer before and after paclitaxel treatment. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system.
  
  
  RESULTS
  In the cell lines, biological response to paclitaxel in vitro did not accurately predict sensitivity to paclitaxel in vivo. Among the breast cancer xenograft tumors, however, tumors with significantly increased CDK1 specific activity after paclitaxel treatment were sensitive to paclitaxel in vivo, whereas tumors without such an increase were resistant to paclitaxel in vivo. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel.
  
  
  CONCLUSIONS
  The change in CDK1 specific activity of xenograft tumors after paclitaxel treatment and the CDK2 specific activity before paclitaxel treatment are both associated with the drug sensitivity in vivo. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.
authors.affiliation: Central Research Laboratories, Sysmex Corporation, 4-4-4, Takatsukadai, Nishi-ku, Kobe, Japan. Nakayama.Satoshi@sysmex.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Torikoshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshida
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sudo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Matsushima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Aya
authors.initials: A
authors.lastname: Katayama
authors.forename: Keigo
authors.initials: K
authors.lastname: Gohda
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Shinzaburo
authors.initials: S
authors.lastname: Noguchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishihara
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002843:Chromatin; D004273:DNA, Neoplasm; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D017239:Paclitaxel