2002 Fiscal Year Final Research Report Summary
Studies on the generation and application of fusion protein of single chain antibody for P-glycoprotein and chemokine
| Project/Area Number |
13557053
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | The University of Tokushima |
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Principal Investigator |
SONE Saburo The University of Tokushima, School of Medicine, Professor, 医学部, 教授 (40145024)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Seiji The University of Tokushima, University Hospital, Assistant Professor, 医学部附属病院, 講師 (30294672)
NISHIOKA Yasuhiko The University of Tokushima, School of Medicine, Assistant Professor, 医学部, 講師 (70274199)
TANI Kenji The University of Tokushima, School of Medicine, Associate Professor, 医学部, 助教授 (70207166)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Multi-drug resistance / P-glycoprotein / MRK16 / single chain antibody |
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| Research Abstract |
The MDR1 gene product P-glycoprotein plays a key role in multidrug resistance of cancer cells. P-glycoprotein is the energy-dependent pump that extrudes a variety of chemotherapeutic drugs. Overexpression of P-glycoprotein results in multidrug resistance of tumor cell lines in vitro as well as in cancer patients. Therefore, much attention has been paid to P-glycoprotein as a molecular target for cancer treatment. MRK16 is the monoclonal antibody against P-glycoprotein and binds to an external domain of P-glycoprotein. It partially inhibits the efflux of certain chemotherapeutic drugs in multidrug-resistant cells, and leads the tumor regression in vivo. Due to the limitations of using intact murine antibodies in human clinical settings, we engineered a single-chain antibody fragment of MRK16 (scFvMRK16). After cloning the variable region of MRK16, both heavy and light chain fragments were fused with linker, and recombinant protein were produced from Escherichia coli. Although the binding activity of scFvMRK16 to P-glycoprotein was 200-300 fold less compared to MRK16, we confirmed by flow cytometric analysis that it does recognize the P-glycoprotein. Furthermore, scFvMRK16 could inhibit the activity of MRK16 to bind P-glycoprotein. These results indicated the therapeutic potential of scFvMRK16.
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[Publications] Goto, H., Yano, S., Zhang, H., Matsumori, Y., Ogawa, H., David C. Blakey., and Sone, S.: "Activity of a New Vascular Targeting Agent, ZD6126, in Pulmonary Metastases by Human Lung Adenocarcinoma in Nude Mice"Cancer Res. 62. 3711-3715 (2002)
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[Publications] Shiraga, M., Yano, S., Yamamoto, A., Ogawa, H., Goto, H., Miki, T., Miki, K., Zhang, H. and Sone, S.: "Organ Heterogeneity of Host-derived Matrix Metalloproteinase Expression and Its Involvement in Multiple-Organ Metastasis by Lung Cancer Cell Lines"Cancer Res. 62. 5967-5973 (2002)
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[Publications] Nishioka, M., Kohno, T., Tani, M., Yanaihara, N., Tomizawa, Y., Otsuka, A., Sasaki, S., Kobayashi, K., Niki, T., Maeshima, A., Sekido, Y., J.D.Minna., Sone, S. and Yokota, J.: "MYO18B, a candidate tumor suppressor gene at chromosome 22q12.1, deleted, mutated, and methylated in human lung cancer."PNAS. 99(19). 12269-12274 (2002)
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[Publications] Yamamoto, A., Yano, S., Shiraga, M., Ogawa, H., Goto, H., Miki, T., Zhang, H. and Sone, S.: "A Third-Generation Matrix Metalloproteinase (MMP) Inhibitor (ONO-4817) Combined with Docetaxel Suppresses Progression of Lung Micrometastasis of MMP-Expressing Tumor Cells in Nude Mice"Int J Cancer. 103. 822-828 (2003)
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