Schedule-dependent synergism and antagonism between pemetrexed and docetaxel in human lung cancer cell lines in vitro |
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Authors: | Yasuhiko Kano Masaru Tanaka Miyuki Akutsu Kiyoshi Mori Yasuo Yazawa Hiroyuki Mano Yusuke Furukawa |
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Institution: | (1) Division of Hematology, Tochigi Cancer Center, Yonan, Utsunomiya Tochigi, 320-0834, Japan;(2) Division of Thoracic Diseases, Tochigi Cancer Center, Utsunomiya Tochigi, 320-0834, Japan;(3) Division of Orthopedic Oncology, Tochigi Cancer Center, Utsunomiya Tochigi, 320-0834, Japan;(4) Division of Functional Genomics, Jichi Medical University, Tochigi 329-0431, Japan;(5) Division of Stem Cell Regulation, Jichi Medical University, Tochigi 329-0431, Japan |
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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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Keywords: | Pemetrexed Docetaxel Isobologram Lung cancer |
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