Low-dose oxaliplatin enhances the antitumor efficacy of paclitaxel in human gastric cancer cell lines.
BACKGROUND
The enhanced antitumor effect of paclitaxel when used with oxaliplatin in gastric cancer is reported, however the underlying biological mechanism is unknown.


METHODS
We tested the cytotoxic activity, apoptosis, and mitotic catastrophe of paclitaxel and oxaliplatin in MKN-28 and MKN-45 gastric cancer cell lines. The modulation of survivin expression was determined by Western blotting.


RESULTS
WST-1 assay indicated that paclitaxel plus oxaliplatin showed better cytotoxicity than paclitaxel alone, even when low concentrations of oxaliplatin were used. Flow cytometry analysis revealed significantly greater increases in apoptotic cells after treatment with paclitaxel followed by low-dose oxaliplatin (1 microM) than after any single-reagent regimen in the MKN-45 cell line. In MKN-28, a difference existed only between combination treatment and oxaliplatin treatment. Morphologic examination showed that the cells undergoing mitotic catastrophe were highest in the combination groups in the both cell lines. Downregulation of survivin expression was found by Western blotting with treatment by paclitaxel, oxaliplatin, or their combination.


CONCLUSIONS
Our findings suggest that the mechanism of enhanced cytotoxicity might be through enhanced mitotic catastrophe and apoptosis, which is possibly due to chemotherapy-induced downregulation of surviving. The combination of paclitaxel and low-dose oxaliplatin should be incorporated into the design of a clinical trial.
Gu
Jinyu
J
Department of Surgery, Gastroenterology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yamamoto
Hirofumi
H
Lu
Xueying
X
Ngan
Chew Yee
CY
Tsujino
Tadashi
T
Konishi
Ken
K
Takemasa
Ichiro
I
Ikeda
Masataka
M
Nagata
Hiroshi
H
Hashimoto
Shusuke
S
Matsuzaki
Takeshi
T
Sekimoto
Mitsugu
M
Takagi
Akimitsu
A
Monden
Morito
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020128:Inhibitory Concentration 50; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin
C107489:BIRC5 protein, human; D015415:Biomarkers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077022:Survivin; D000077150:Oxaliplatin; D017239:Paclitaxel