Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models.
OBJECTIVE
To clarify the antitumor activity of trastuzumab and its potential as an effective treatment for gastric cancer patients.


METHODS
Levels of HER2 expression in tumor tissues of gastric cancer cell lines were examined using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and mRNA quantification. Efficacy of trastuzumab was examined as a single agent or in combination with chemotherapeutic agents widely used clinically for gastric cancers in HER2-overexpressing human gastric cancer xenograft models.


RESULTS
Two of nine human gastric cancer xenograft models, NCI-N87 and 4-1ST, showed overexpression of HER2 mRNA and protein by IHC (HercepTest) and HER2 gene amplification by FISH (Pathvysion). HER2 protein showed potent staining in peripheral membranes, similar to the staining pattern of breast cancer. FISH scores were also comparable to those of breast cancer models. Trastuzumab as a single agent inhibited the tumor growth in both of the HER2-overexpressing models but not in the HER2-negative models, GXF97 and MKN-45. In any combination with capecitabine, cisplatin, irinotecan, docetaxel, or paclitaxel, trastuzumab showed more potent antitumor activity than the anticancer agents alone. A three-drug combination of capecitabine, cisplatin, and trastuzumab showed remarkable tumor growth inhibition. In NCI-N87 in vitro, trastuzumab showed direct antiproliferative activity according to cell count or crystal violet dying, and showed indirect antitumor activity such as antibody-dependent cellular cytotoxicity.


CONCLUSIONS
The antitumor activity of trastuzumab observed in human gastric cancer models warrants consideration of its use in clinical treatment regimens for human gastric cancer as a single agent or a combination drug with various chemotherapeutic agents.
Fujimoto-Ouchi
Kaori
K
Product Research Department, Kamakura Research Center, Chugai Pharmaceuticals Co., Ltd, 200 Kajiwara Kamakura, Kanagawa, 247-8530, Japan. ohuchikor@chugai-pharm.co.jp
Sekiguchi
Fumiko
F
Yasuno
Hideyuki
H
Moriya
Yoichiro
Y
Mori
Kazushige
K
Tanaka
Yutaka
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab