Cytotoxic Effects of 27 Anticancer Drugs in HeLa and MDR1-Overexpressing Derivative Cell Lines

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Abstract

The cytotoxic effects of 27 anticancer drugs including amrubicin, vinorelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan were evaluated in human cervical carcinoma HeLa cells, and drug-resistant HeLa-derived Hvr1-1, Hvr10-6, and Hvr100-6 cells, which were newly established by stepwise exposure to vinblastine. FACS and RT-PCR analysis indicated that MDR1 (P-glycoprotein) was induced without any alterations in expression of its related transporters. Hvr100-6 cells showed 2- to 200-fold higher resistance to anthracyclines than HeLa cells, and unexpectedly showed slight resistance to idarubicin and amrubicin. The relative resistance to <i>vinca</i>-alkaloids was 300- to 600000-fold, and Hvr100-6 cells showed the highest relative resistance to vinorelbine. Hvr100-6 cells also showed 4000- and 60000-fold resistance to the taxanes paclitaxel and docetaxel, respectively. Hvr100-6 cells were also resistant to 6-mercaptopurine, actinomycin D, etoposide, and mitomycin C, with relative resistance of 8-, 45000-, 12-, and 9-fold, respectively. In contrast, Hvr100-6 cells showed no or slight resistance to platinum derivatives, pyrimidine analogues, and alkylating agents or to irinotecan and its active form, or tamoxifen. The cytotoxicity of anthracyclines, <i>vinca</i>-alkaloids, taxanes, actinomycin D, and etoposide was extensively reversed by cyclosporin A. Cyclosporin A had no effect on the cytotoxicity of 6-mercaptopurine or mitomycin C, suggesting that resistance to these drugs was not mediated <i>via</i> MDR1. The alterations in cytotoxicity by overexpression of MDR1 and effects of cyclosporin A could be also qualitatively explained by [<sup>3</sup>H]vinblastine uptake experiments. The 27 anticancer drugs analyzed here could be classified into substrates and nonsubstrates for MDR1. This will be useful for designing effective regimens for chemotherapy.

Journal

  • Biological and Pharmaceutical Bulletin

    Biological and Pharmaceutical Bulletin 25(6), 771-778, 2002-06-01

    The Pharmaceutical Society of Japan

References:  39

Cited by:  4

Codes

  • NII Article ID (NAID)
    110003638755
  • NII NACSIS-CAT ID (NCID)
    AA10885497
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    09186158
  • NDL Article ID
    6175089
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-V41
  • Data Source
    CJP  CJPref  NDL  NII-ELS  J-STAGE 
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