In vitro schedule-dependent interaction between paclitaxel and oxaliplatin in human cancer cell lines.
OBJECTIVE
In order to define the most effective administration schedule of the combination of paclitaxel and oxaliplatin, we investigated the in vitro interaction between these drugs in a panel of three human cancer cell lines (AZ-521 gastric adenocarcinoma cell line, HST-1 tongue squamous carcinoma cell line, and KSE-1 esophageal squamous carcinoma cell line).


METHODS
Cytotoxic activity was determined by the WST-1 assay. Different administration schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry.


RESULTS
Simultaneous treatment of cells with paclitaxel and oxaliplatin showed greater than additive effects. Upon 24-h sequential exposure, the sequence of paclitaxel followed by oxaliplatin showed synergistic effects in AZ-521 and HST-1 cells, and greater than additive effects in KSE-1 cells, while the opposite sequence yielded marked antagonistic effects in all three cell lines. Flow cytometric analysis indicated that paclitaxel induced G(2)/M arrest with subsequent induction of apoptosis in the sub-G(1) phase. Apoptosis was most prominent when paclitaxel preceded oxaliplatin, which produced apoptosis in the majority of treated cells (75%). By contrast, the reverse sequence yielded only 39% induction of apoptotic cells, the rate being not different from those induced by each drug singly.


CONCLUSIONS
Our findings suggest that the interaction of paclitaxel and oxaliplatin is highly schedule-dependent and that the sequential administration of paclitaxel followed by oxaliplatin should thus be incorporated into the design of a clinical trial.
Tanaka
Risa
R
First Department of Internal Medicine, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Ariyama
Hiroshi
H
Qin
Baoli
B
Takii
Yasushi
Y
Baba
Eishi
E
Mitsugi
Kenji
K
Harada
Mine
M
Nakano
Shuji
S
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology*
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel