title: Activation of DNA damage response by antitumor therapy counteracts the activity of vinca alkaloids.
abstract: OBJECTIVE
  Anthracyclines have been proven able to reduce the activity of vinca alkaloids by induction of cell-cycle arrest. The present study aims at identifying the critical initiation steps of signal transduction which transduce the inhibitory effects on the cytotoxicity of vinca alkaloids.
  
  
  METHODS
  Several new cytostatic drug classes were evaluated together with vincristine in tumor cell lines and patients' tumor cells. RNA interference was used for molecular analyses.
  
  
  RESULTS
  Inhibition of vincristine was observed by all cytostatic drugs, which induced cell-cycle arrest. Knockdown of proteins of the DNA damage response ascribed the inhibitory effect to a common pathway involving Chk-1, p53 and p21. Upstream of Chk-1 signal transduction depended on both ATM and ATR for all drugs except methotrexate.
  
  
  CONCLUSIONS
  We have identified critical signaling steps of the DNA damage response system activated by cytostatic drugs, which reduce the anti-tumor activity of vinca alkaloids. The obtained results encourage the development of novel therapeutic strategies to prevent pathway interactions based on the molecular understanding of drug action and drug-drug interactions.
authors: Helmholtz Center Munich, German Research Center for Environmental Health, Marchioninistrasse 25, D-81377 München, Germany. Harald.Ehrhardt@helmholtz-muenchen.de.
authors: Harald
authors: H
authors: Ehrhardt
authors: Sarah
authors: S
authors: Pfeiffer
authors: David
authors: D
authors: Schrembs
authors: Franziska
authors: F
authors: Wachter
authors: Michaela
authors: M
authors: Grunert
authors: Irmela
authors: I
authors: Jeremias
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D017931:DNA Primers; D006801:Humans; D014750:Vincristine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D014750:Vincristine
keywords: ATM; ATR; Chk1; DNA damage; cell-cycle arrest; p21; p53; vinca alkaloids