期刊
ANTI-CANCER DRUGS
卷 25, 期 3, 页码 315-322出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0000000000000048
关键词
excision repair cross-complementation group 1; gastric cancer; oxaliplatin; trastuzumab
资金
- National Natural Science Foundation of China [81172369, 81172198, 81372485, 31000607]
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2013ZX09303002]
- Program for Liaoning Excellent Talents in University, LNET [LJQ2011082]
- The Key Laboratory Project of Liaoning Provincial Education Department [LS2010169]
Trastuzumab has recently been recommended for the treatment of epidermal growth factor receptor-2 (HER2)-positive advanced gastric cancer in combination with the capecitabine/cisplatin (XP) versus continuous infusion of 5-fluorouracil/cisplatin (FP) regimen. However, it is unclear whether it is rational to combine trastuzumab with other chemotherapy regimens in clinical practice. Our study demonstrates that adding trastuzumab to oxaliplatin, a commonly used third-generation platinum derivative, increases the antitumor effect in vitro. In MTT assays, combination treatment with oxaliplatin and trastuzumab significantly decreased the concentration of oxaliplatin required to induce 50% growth inhibition in HER2-positive gastric cancer cells. Further investigation revealed that the trastuzumab-oxaliplatin combination induced cell cycle arrest and decreased expression of both p-AKT and p-ERK. Notably, this treatment combination induced downregulation of the excision repair cross-complementation group 1 (ERCC1) protein, which is involved in the key repair process of the oxaliplatin-DNA platinum adduct at the protein level. Similar changes were also observed in HER2-positive breast cancer cells. These findings suggest that trastuzumab synergizes the cytotoxic effect of oxaliplatin on HER2-positive gastric and breast cancer cells. Our study provides preclinical evidence for the optimization of this combination regimen in the treatment of HER2-positive gastric cancer patients.
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