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Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines.
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MedLine Citation:
PMID:  10993656     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0-2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 x IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 x IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70-89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine-paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences.
Authors:
J R Kroep; G Giaccone; C Tolis; D A Voorn; W J Loves; C J Groeningen; H M Pinedo; G J Peters
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of cancer     Volume:  83     ISSN:  0007-0920     ISO Abbreviation:  Br. J. Cancer     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-11-03     Completed Date:  2000-11-03     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0370635     Medline TA:  Br J Cancer     Country:  SCOTLAND    
Other Details:
Languages:  eng     Pagination:  1069-76     Citation Subset:  IM    
Copyright Information:
Copyright 2000 Cancer Research Campaign.
Affiliation:
Department of Medical Oncology, University Hospital Vrije Universiteit, P.O Box 7057, Amsterdam, MB, 1007, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimetabolites, Antineoplastic / pharmacokinetics,  toxicity*
Biotransformation
Carcinoma, Non-Small-Cell Lung
Cell Cycle / drug effects,  physiology*
Cell Division / drug effects
Cell Survival / drug effects
DNA, Neoplasm / biosynthesis
Deoxycytidine / analogs & derivatives*,  pharmacokinetics,  toxicity
Humans
Kinetics
Lung Neoplasms
Mice
Paclitaxel / toxicity*
RNA, Neoplasm / biosynthesis
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/DNA, Neoplasm; 0/RNA, Neoplasm; 33069-62-4/Paclitaxel; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Br J Cancer
ISSN: 0007-0920
ISSN: 1532-1827
Publisher: Nature Publishing Group
Article Information
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Copyright 2000, Cancer Research Campaign
Received Day: 02 Month: 03 Year: 2000
Revision Received Day: 22 Month: 06 Year: 2000
Accepted Day: 28 Month: 06 Year: 2000
Print publication date: Month: 10 Year: 2000
Volume: 83 Issue: 8
First Page: 1069 Last Page: 1076
ID: 2363564
Publisher Item Identifier: 6691399
DOI: 10.1054/bjoc.2000.1399
PubMed Id: 10993656

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines
J R Kroep1
G Giaccone1
C Tolis1
D A Voorn1
W J P Loves1
C J van Groeningen1
H M Pinedo1
G J Peters1
1Department of Medical Oncology, University Hospital Vrije Universiteit, P.O Box 7057, Amsterdam, MB, 1007, The Netherlands


Article Categories:
  • Regular Article

Keywords: gemcitabine, paclitaxel, NSCLC cell lines, cell cycle, cytotoxicity, dFdCTP.

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