論文 - 詳細
RRC ID | 51609 |
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著者 | Ito K, Mitsunaga M, Arihiro S, Saruta M, Matsuoka M, Kobayashi H, Tajiri H. |
タイトル | Molecular targeted photoimmunotherapy for HER2-positive human gastric cancer in combination with chemotherapy results in improved treatment outcomes through different cytotoxic mechanisms. |
ジャーナル | BMC Cancer |
Abstract |
BACKGROUND:Photoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light. PIT rapidly causes target-specific cell death by inducing cell membrane damages and appears to be highly effective; however, we have previously demonstrated that tumor recurrences were eventually seen in PIT-treated mice, likely owing to inhomogeneous mAb-IR700 conjugate distribution in the tumor, thus limiting the effectiveness of PIT as a monotherapy. Here, we examined the effects of human epidermal growth factor-2 (HER2)-targeted PIT in combination with 5-fluorouracil (5-FU) compared to PIT alone for HER2-expressing human gastric cancer cells. METHODS:NCI-N87 cells, HER2-positive human gastric cancer cells, were used for the experiments. Trastuzumab, a monoclonal antibody directed against HER2, was conjugated to IR700. To assess the short-term cytotoxicity and examine the apoptotic effects upon addition of 5-FU in vitro, we performed LIVE/DEAD and caspase-3 activity assays. Additionally, to explore the effects on long-term growth inhibition, trypan blue dye exclusion assay was performed. NCI-N87 tumor xenograft models were prepared for in vivo treatment studies and the tumor-bearing mice were randomized into various treatment groups. RESULTS:Compared to PIT alone, the combination of HER2-targeted PIT and 5-FU rapidly induced significant cytotoxicity in both the short-term and long-term cytotoxicity assays. While both 5-FU and/or trastuzumab-IR700 conjugate treatment induced an increase in caspase-3 activity, there was no additional increase in caspase-3 activity upon NIR light irradiation after incubation with 5-FU and/or trastuzumab-IR700. The combination of HER2-targeted PIT and 5-FU resulted in greater and longer tumor growth inhibition than PIT monotherapy in vivo. This combined effect of PIT and 5-FU is likely owing to their different mechanisms of inducing tumor cell death, namely necrotic membrane damage by PIT and apoptotic cell death by 5-FU and trastuzumab. CONCLUSIONS:PIT in combination with 5-FU resulted in enhanced antitumor effects compared to PIT alone for HER2-expressing human gastric cancer in vitro and in vivo. This combination photoimmunochemotherapy represents a practical method for treating human gastric cancer and should be investigated further in the clinical setting. |
巻・号 | 16 |
ページ | 37 |
公開日 | 2016-1-25 |
DOI | 10.1186/s12885-016-2072-0 |
PII | 10.1186/s12885-016-2072-0 |
PMID | 26810644 |
PMC | PMC4727331 |
MeSH | Animals Apoptosis / drug effects Cell Line, Tumor Combined Modality Therapy Fluorouracil / administration & dosage Humans Immunotherapy / methods* Mice Molecular Targeted Therapy* Phototherapy / methods* Receptor, ErbB-2 / genetics* Receptor, ErbB-2 / immunology Stomach Neoplasms / genetics Stomach Neoplasms / immunology* Stomach Neoplasms / pathology Stomach Neoplasms / therapy* Trastuzumab / administration & dosage Treatment Outcome Xenograft Model Antitumor Assays |
IF | 3.15 |
引用数 | 14 |
リソース情報 | |
ヒト・動物細胞 | MKN45(RCB1001) |