Targeting Angiogenesis and HGF Function Using an Adenoviral Vector Expressing the HGF Antagonist NK4 for Cancer Therapy
| Autor: | Toshikazu Nakamura, Yasuo Saijo, Kazuhiro Usui, Ryushi Tazawa, Minoru Tahara, Makoto Maemondo, Koichi Hagiwara, Kunio Matsumoto, Toshihiro Nukiwa, Ko Narumi |
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| Rok vydání: | 2002 |
| Předmět: |
Lung Neoplasms
Angiogenesis Genetic enhancement Mice Nude Apoptosis Adenoviridae Cell Line Metastasis Neovascularization Mice In vivo Drug Discovery medicine Genetics Animals Humans Molecular Biology Pharmacology Neovascularization Pathologic Hepatocyte Growth Factor Chemistry Gene Transfer Techniques Cancer Genetic Therapy medicine.disease Molecular biology Angiogenesis inhibitor Molecular Medicine Hepatocyte growth factor Mitogens medicine.symptom medicine.drug |
| Zdroj: | Molecular Therapy. 5(2):177-185 |
| ISSN: | 1525-0016 |
| DOI: | 10.1006/mthe.2002.0533 |
| Popis: | Hepatocyte growth factor (HGF) affects tumor growth/invasion and tumor neovascularization. A proposed HGF antagonist, NK4 (an amino-terminal kringle-domain peptide of HGF), inhibits tumor growth/invasion through the competition of HGF binding to its receptor, c-Met, and acts as an angiogenesis inhibitor. To investigate the in vivo effect of NK4 gene transfer, we constructed an adenovirus vector expressing human NK4 (AdCMV.NK4). Human lung cancer cell lines (A549 and H358) infected in vitro with AdCMV.NK4 yielded NK4 protein without a change in the cell growth rate. In contrast, direct injection of AdCMV.NK4 (1 x 10(9) pfu, twice) into established subcutaneous tumors in BALB/c nu/nu mice resulted in suppression of the tumors by 64% for A549 or by 91% for H358 compared with controls (P0.02 or P0.01, respectively). Counting of the tumor vessels revealed suppressed vascularity by 57% in H358 tumors when using AdCMV.NK4 (P0.0001). Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P0.032), subcutaneous tumor growth in vivo (by 65% for H358, P0.001), and hematogenous lung metastases without obvious side effects. These results indicate that NK4 elicits tumor-growth suppression in vivo through its anti-angiogenic activity and anti-HGF activity and that NK4 gene transfer can be an effective tool in the treatment of cancer. |
| Databáze: | OpenAIRE |
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