Document Detail


Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies.
MedLine Citation:
PMID:  23186127     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 drug-drug interactions.
LINKED ARTICLE: 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:
H Ehrhardt; L Pannert; S Pfeiffer; F Wachter; E Amtmann; I Jeremias
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1558-69     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anthracyclines / pharmacology*,  therapeutic use
Antineoplastic Agents / pharmacology*,  therapeutic use
Antineoplastic Combined Chemotherapy Protocols / pharmacology,  therapeutic use
Apoptosis / drug effects,  radiation effects
Cell Cycle Checkpoints / drug effects,  radiation effects
Cell Division / drug effects,  radiation effects
Cell Line, Tumor
Dexamethasone / pharmacology*,  therapeutic use
Doxorubicin / pharmacology,  therapeutic use
Drug Antagonism
Female
Gamma Rays
Humans
Mice
Mice, Nude
Mitosis / drug effects,  radiation effects
Neoplasm Transplantation
Vincristine / pharmacology*,  therapeutic use
Chemical
Reg. No./Substance:
0/Anthracyclines; 0/Antineoplastic Agents; 57-22-7/Vincristine; 7S5I7G3JQL/Dexamethasone; 80168379AG/Doxorubicin
Comments/Corrections
Comment In:
Br J Pharmacol. 2013 Apr;168(7):1555-7   [PMID:  23316995 ]

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