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Ehrhardt, H. ; Pannert, L. ; Pfeiffer, S. ; Wachter, F. ; Amtmann, E.* ; Jeremias, I.

Enhanced anti-tumour effects of vinca alkaloids given separately from cytostatic therapies.

Br. J. Pharmacol. 168, 1558-1569 (2013)
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Background and Purpose 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. Experimental Approach 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. Key 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. Conclusion and Implications 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 drugdrug interactions.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Doxorubicin ; Vincristine ; P53 ; Cell Cycle Arrest ; Application Schedule; Cell-cycle Arrest ; Tumor-cells ; Cancer-therapy ; Arrive Guidelines ; Drug-combinations ; Breast-cancer ; Dna-damage ; In-vitro ; Apoptosis ; P53
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Zeitschrift British Journal of Pharmacology
Quellenangaben Band: 168, Heft: 7, Seiten: 1558-1569 Artikelnummer: , Supplement: ,
Verlag Wiley
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501590-001
PubMed ID 23186127
DOI 10.1111/bph.12068
WOS ID WOS:000316262500003
Scopus ID 84875144889
Erfassungsdatum 2013-04-11
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