A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma
| Autor: | Tetsuji Sawada, Masashige Tendo, Yoshio Hamashima, Tetsuya Kajimoto, Manabu Node, Hidemi Kawajiri, Kosei Hirakawa, Kazunori Nakamura, Satoru Takemura, Osamu Shinto, Masakazu Yashiro, Masaichi Ohira |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Integrins
Cancer Research Pathology medicine.medical_specialty Adenocarcinoma Scirrhous Integrin Mice Nude Antineoplastic Agents Smad2 Protein Mice Peritoneum Stomach Neoplasms Fibrosis Cell Line Tumor Cell Adhesion medicine Animals Humans Neoplasm Invasiveness Neoplasm Metastasis Phosphorylation RNA Small Interfering Fibroblast Peritoneal Neoplasms Cell Proliferation Mice Inbred BALB C biology Cell adhesion molecule business.industry Cancer medicine.disease medicine.anatomical_structure Oncology Cancer cell Quinolines biology.protein Pyrazoles Female business Receptors Transforming Growth Factor beta Transforming growth factor |
| Zdroj: | Clinical Cancer Research. 14:2850-2860 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Transforming growth factor β receptor (TGFβ-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFβ-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer. Experimental Design: Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro. Results: The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of α2, α3, and α5 integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells. Conclusion: The TGFβ-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma. |
| Databáze: | OpenAIRE |
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