title: Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies.
abstract: OBJECTIVE
  In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested.
  
  
  METHODS
  Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference.
  
  
  RESULTS
  In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics.
  
  
  CONCLUSIONS
  Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug-drug interactions.
  
  
  BACKGROUND
  This article is commented on by Solary, pp 1555-1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101.
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrhardt
authors.forename: L
authors.initials: L
authors.lastname: Pannert
authors.forename: S
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: F
authors.initials: F
authors.lastname: Wachter
authors.forename: E
authors.initials: E
authors.lastname: Amtmann
authors.forename: I
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004336:Drug Antagonism; D005260:Female; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D009368:Neoplasm Transplantation; D014750:Vincristine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin