The sequence-dependent cytotoxic effect of trastuzumab in combination with 5-Fluorouracil or cisplatin on gastric cancer cell lines.
The effect of trastuzumab on patients with HER-2/neu (HER2)-positive gastric cancer has been confirmed in a phase III clinical trial (ToGA study). However, the optimized sequence and synergic mechanism of trastuzumab and chemotherapy are not clear. Our study investigated the effects and mechanisms of trastuzumab in combination with 5-Fluorouracil (5-Fu) or cisplatin (DDP) on gastric cancer cell lines. Flow cytometry was used to determine HER2 expression and cell cycle. MTT assay was performed to evaluate cytotoxicity. Western blotting and RT-PCR were used to analyze signaling transduction and mRNA expression. Sequential 5-Fu followed by trastuzumab and trastuzumab plus DDP followed by trastuzumab produced the best inhibitory effects. Inhibition of HER2-PI3K-AKT signal transduction, downregulation of nucleotide excision repair cross-complementation 1 (ERCC1), and interference with cell cycle distribution may elucidate the synergism between trastuzumab and chemotherapy. These results provide some evidence for designing a rational regime when trastuzumab is being considered to be used in patients with gastric cancer.
Li
Xiao-Ling
XL
Department of Pharmacy, Xuanwu Hospital, Capital Medical University, Beijing, China.
Yi
Shao-Qiong
SQ
Xu
Jian-Ming
JM
Zhang
Yang
Y
Yingying-Feng
Chen
Wei
W
Song
San-Tai
ST
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002469:Cell Separation; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004720:Endonucleases / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002945:Cisplatin; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005472:Fluorouracil; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C071447:ERCC1 protein, human