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Research ArticleArticle

Gemcitabine Potentiates Cisplatin Cytotoxicity and Inhibits Repair of Cisplatin-DNA Damage in Ovarian Cancer Cell Lines

Mazin A. Moufarij, Don R. Phillips and Carleen Cullinane
Molecular Pharmacology April 2003, 63 (4) 862-869; DOI: https://doi.org/10.1124/mol.63.4.862
Mazin A. Moufarij
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Don R. Phillips
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Carleen Cullinane
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Abstract

Synergistic cytotoxicity between cisplatin and the nucleoside analog gemcitabine was observed in a panel of cisplatin-sensitive (2008, A2780) and -resistant (2008/C13*5.25, A2780/CP70) human ovarian cell lines. Previous studies have suggested a role for DNA repair in the mechanism of synergy between the two drugs. We therefore further investigated the hypothesis that the synergistic cytotoxicity between gemcitabine and cisplatin in these cell lines may be caused by gemcitabine-mediated inhibition of cisplatin intrastrand adduct (IA) and interstand cross-link (ICL) repair. The effect of gemcitabine on the accumulation and repair of cisplatin IA and ICL in each cell line was then measured directly using gene-specific quantitative polymerase chain reaction and denaturation/renaturation techniques, respectively. Pretreatment of 2008 cells with 1 μM gemcitabine for 2 h before exposure to cisplatin for 7 h enhanced the accumulation of cisplatin IA and ICL by 50 and 40%, respectively (P < 0.05), above that induced by cisplatin alone. To investigate the possibility that the increased accumulation of cisplatin lesions was caused by inhibition of removal of cisplatin damage, 2008 cells were incubated with 200 μM cisplatin for 5 h in the presence and absence of gemcitabine and then a further 8 h in the absence of cisplatin. Only 57% IA were removed in the combination treated cells compared with 74% in cisplatin control cells. Similarly, repair of cisplatin ICL was inhibited in the gemcitabine-treated cells compared with the cells treated with cisplatin only (60 versus 72%). These findings demonstrate a direct inhibitory effect of gemcitabine on the repair of cisplatin IA and ICL and suggest a mechanistic basis for the cytotoxic synergy between the two drugs.

Footnotes

  • This work was supported in part by a research grant from ANZ Trustees (C.C), and an Australian Postgraduate Award scholarship (M.A.M).

  • Abbreviations:
    NSCLC
    non–small-cell lung cancer
    CI
    combination index
    kb
    kilobase(s)
    DRI
    dose-reduction index
    PCR
    polymerase chain reaction
    QPCR
    quantitative polymerase chain reaction
    ICL
    interstrand cross-link
    IA
    intrastrand adduct
    DHFR
    dihydrofolate reductase
    • Received October 16, 2002.
    • Accepted January 13, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (4)
Molecular Pharmacology
Vol. 63, Issue 4
1 Apr 2003
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Research ArticleArticle

Gemcitabine Potentiates Cisplatin Cytotoxicity and Inhibits Repair of Cisplatin-DNA Damage in Ovarian Cancer Cell Lines

Mazin A. Moufarij, Don R. Phillips and Carleen Cullinane
Molecular Pharmacology April 1, 2003, 63 (4) 862-869; DOI: https://doi.org/10.1124/mol.63.4.862

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Research ArticleArticle

Gemcitabine Potentiates Cisplatin Cytotoxicity and Inhibits Repair of Cisplatin-DNA Damage in Ovarian Cancer Cell Lines

Mazin A. Moufarij, Don R. Phillips and Carleen Cullinane
Molecular Pharmacology April 1, 2003, 63 (4) 862-869; DOI: https://doi.org/10.1124/mol.63.4.862
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