Schedule-dependent synergism and antagonism between pemetrexed and docetaxel in human lung cancer cell lines in vitro.
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.
Kano
Yasuhiko
Y
Division of Hematology, Tochigi Cancer Center, Yonan, Utsunomiya, Tochigi 320-0834, Japan. ykano@tcc.pref.tochigi.jp
Tanaka
Masaru
M
Akutsu
Miyuki
M
Mori
Kiyoshi
K
Yazawa
Yasuo
Y
Mano
Hiroyuki
H
Furukawa
Yusuke
Y
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005971:Glutamates / Q000008:administration & dosage* / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D000068437:Pemetrexed; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology*; D013997:Time Factors
D005971:Glutamates; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D006147:Guanine