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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Cellular Pharmacokinetic/Pharmacodynamic Relationship of Platinum Cytostatics in Head and Neck Squamous Cell Carcinoma Evaluated by Liquid Chromatography Coupled to Tandem Mass Spectrometry

Dirk Theile, Jan-Christoph Detering, Christel Herold-Mende, Gerhard Dyckhoff, Walter E. Haefeli, Johanna Weiss and Jürgen Burhenne
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 51-58; DOI: https://doi.org/10.1124/jpet.111.189621
Dirk Theile
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Jan-Christoph Detering
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Christel Herold-Mende
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Gerhard Dyckhoff
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Walter E. Haefeli
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Johanna Weiss
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Jürgen Burhenne
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Abstract

Cisplatin (diaminodichloroplatinum) is the favored platinum (Pt) drug for the treatment of head and neck squamous cell carcinoma (HNSCC). However, Pt drug alternatives such as carboplatin (diaminoplatinum-cyclobutan-1,1-dicarboxylate) or oxaliplatin [oxalato[(1R,2R)-cyclohexanediamino]platinum] have not been comprehensively investigated in HNSCC. Moreover, little data reveal the decisive efficacy determinant and whether Pt drug efficacy is truly concentration-dependent. Using five human HNSCC cell lines, we determined the concentrations of cisplatin, carboplatin, and oxaliplatin leading to 50% inhibition of cell proliferation (IC50). Concurrently we quantified cellular drug uptake by liquid chromatography coupled to tandem mass spectrometry and evaluated mRNA expression of drug transporters involved in Pt drug uptake by quantitative real-time polymerase chain reaction. Mean IC50 among the five cell lines was 6.2 ± 1.9 μM for cisplatin and 11.6 ± 4.2 μM for oxaliplatin, whereas carboplatin showed significantly lower proliferation inhibition (IC50 107.5 ± 21.2 μM). In agreement with this finding carboplatin poorly accumulated in HNSCC cells, compared with cisplatin and oxaliplatin. HNSCC cell lines expressed Pt drug transporters. Taken together, the results demonstrate: 1) carboplatin was less effective and was poorly taken up; 2) a high individuality among cell lines was found concerning the accumulation of cisplatin and oxaliplatin despite similar in vitro efficacy; and 3) distinct expression of SLC22A2 and ABCC2 accompanies strong uptake and cytotoxicity of Pt drugs. In conclusion, we demonstrate that in vitro efficacy of cisplatin and oxaliplatin in HNSCC is concentration-independent because they exhibited different uptake characteristics but similar efficacies, suggesting oxaliplatin as a promising alternative against HNSCC that needs further evaluation in clinical trials.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.189621.

  • ABBREVIATIONS:

    HNSCC
    head and neck squamous cell carcinoma
    Pt
    platinum
    Pd
    palladium
    5-FU
    5-fluorouracil
    DDTC
    diethyldithiocarbamate
    SLC
    solute carrier
    OCT
    organic cation transporter
    MRP2
    multidrug resistance-associated protein 2
    ANOVA
    analysis of variance
    AUC
    area under the curve
    QC
    quality control
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    ESI
    electrospray ionization
    PBS
    phosphate-buffered saline
    RPL13
    ribosomal protein L13.

  • Received November 1, 2011.
  • Accepted December 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Platinum Drug Uptake and Efficacy in Head and Neck Cancer

Dirk Theile, Jan-Christoph Detering, Christel Herold-Mende, Gerhard Dyckhoff, Walter E. Haefeli, Johanna Weiss and Jürgen Burhenne
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 51-58; DOI: https://doi.org/10.1124/jpet.111.189621

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Platinum Drug Uptake and Efficacy in Head and Neck Cancer

Dirk Theile, Jan-Christoph Detering, Christel Herold-Mende, Gerhard Dyckhoff, Walter E. Haefeli, Johanna Weiss and Jürgen Burhenne
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 51-58; DOI: https://doi.org/10.1124/jpet.111.189621
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