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Schedule-dependent synergism and antagonism between pemetrexed and docetaxel in human lung cancer cell lines in vitro

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Abstract

Background

Pemetrexed and docetaxel show clinical activities against a variety of solid tumors including lung cancers. To identify the optimal schedule for combination, cytotoxic interactions between pemetrexed and docetaxel were studied at various schedules using three human lung cancer cell lines A-549, Lu-99, and SBC-5 in vitro.

Methods

Cells were incubated with pemetrexed and docetaxel simultaneously for 24 or 120 h. Cells were also incubated with pemetrexed for 24 h, followed by a 24 h exposure to docetaxel, and vice versa. Growth inhibition was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis. Cytotoxic interactions were evaluated by the isobologram method.

Results

Simultaneous exposure to pemetrexed and docetaxel for 24 and 120 h produced antagonistic effects in all three cell lines. Pemetrexed (24 h) followed by docetaxel (24 h) produced additive effects in A-549 cells and synergistic effects in Lu-99 and SBC-5 cells. Docetaxel followed by pemetrexed produced additive effects in A-549 and Lu-99 cells and antagonistic effects in SBC-5 cells. The results of cell cycle analysis were fully consistent with those of isobologram analysis, and provide the molecular basis of the sequence-dependent difference in cytotoxic interactions between the two agents.

Conclusions

Sequential administration of pemetrexed followed by docetaxel may provide the greatest anti-tumor effects for this combination in the treatment of lung cancer.

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Acknowledgment

This work was supported in part by a Grant for Third-Term-Comprehensive Control Research for Cancer from the in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.

Conflict of interest statement

None.

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Authors and Affiliations

  1. Division of Hematology, Tochigi Cancer Center, Yonan, Utsunomiya, Tochigi, 320-0834, Japan

    Yasuhiko Kano, Masaru Tanaka & Miyuki Akutsu

  2. Division of Thoracic Diseases, Tochigi Cancer Center, Utsunomiya, Tochigi, 320-0834, Japan

    Kiyoshi Mori

  3. Division of Orthopedic Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, 320-0834, Japan

    Yasuo Yazawa

  4. Division of Functional Genomics, Jichi Medical University, Tochigi, 329-0431, Japan

    Hiroyuki Mano

  5. Division of Stem Cell Regulation, Jichi Medical University, Tochigi, 329-0431, Japan

    Yusuke Furukawa

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  1. Yasuhiko Kano
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Correspondence to Yasuhiko Kano.

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Kano, Y., Tanaka, M., Akutsu, M. et al. Schedule-dependent synergism and antagonism between pemetrexed and docetaxel in human lung cancer cell lines in vitro. Cancer Chemother Pharmacol 64, 1129–1137 (2009). https://doi.org/10.1007/s00280-009-0974-0

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  • DOI: https://doi.org/10.1007/s00280-009-0974-0

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