The research for the mechanism of resistance to catalytic topoisomerase II inhibitors
| Project/Area Number |
09671236
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Fukuoka Dental College |
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Principal Investigator |
KUSUMOTO Hiroki Fukuoka Dental College, Dept. of Surgery, Assistant Professor (00195447)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Shinji Kyushu University, Medical Institute of Bioregulation, Assistant (30253420)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | topoisomerases / anticancer drug / cell cycle / topoisomerasell / cyclin B / p53 / topoisomerase II |
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| Research Abstract |
We have established resistant cell lines (RC lines) to merbarone, a catalytic topoisomerase II inhibitor, from the human leukemic CEM cells. We have realized so far the following fmdings. (1)There is a cross-resistance to complex-stabilizing inhibitors in the RC lines. (2)However, complex-stabilizing activity is not concerned to the resistance mechanism. (3)Pgp or mrp does not participated in the mechanism, either. (4)Topo I activity is increased in the RC lines. (5)There is a point mutation at the promoter site of topo II gene in the RC lines. (6)When the cells are cultured synchronously, the degree of inhibition of G2/M transition in the cell cycle by the cytostatic topo II inhibitiors is lower in the RC lines than the sensitive cell lines. (7)The expression of P53 protein is decreased, but that of P21 is not in the RC lines, compared to the sensitive lines. (8)Irregular chromatin and topo II localization in the nucleus is found in the RC lines at the mitotic phase. (9)Regulation by 14-3-3, Chk25 or Chk1 may not be the factors of the difference of cellular attitude at the mitotic phase between these cell lines.
According to these results, we can hypothesize the existence of checkpoint mechanism at the mitotic phase in RC lines that is regulated by P53, but not by P21. Apart from the complex-stabilizing enzymatic mechanism of topo II, there might be a cytotoxic mechanism of topo II inhibitors that affects topo II as a constructive nuclear protein at the M phase. The resistance in RC lines might be concerned, in part, with a difference of degree of destruction of topo II, a structural protein of the nucleus.
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Report
(3 results)
Research Products
(27 results)
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[Journal Article] P53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM celli2000
Author(s)
Morgan, S. E., Kim, R., Wang, P. C., Bhat, U. G., Kusumoto, H., Lu, T., Beck, W. T.
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Journal Title
Oncogene 43
Pages: 5010-9
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Clinica implications of serum anti-P53 antibodies for patients with gastric carcinoma.1999
Author(s)
Maehara, Y., Kakeji, Y., Watanabe, A., Baba, H., Kusumoto, H., Kohnoe, S., Sugimachi, K.
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Journal Title
Description
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[Journal Article] Biologic significance o angiopoietin-2 expression in human hepatocellular carcinoma.1999
Author(s)
Tanaka, S., Mori, M., Sakamoto, Y., Makuuchi, M., Sugimachi, K., Wands, J. R.
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Journal Title
J. Clin. Investigation 103
Pages: 341-5
Description
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[Journal Article] A novel varian of human Grb7 is associated with invasive esophageal carcinoma.1998
Author(s)
Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, 3. R., Sugimachi, K.
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Journal Title
3. Clin. Invest. 102
Pages: 821-7
Description
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[Journal Article] Analysis of orrnthine decarboxilase mRNA expression in colorectal carcinoma.1997
Author(s)
Mimori, K., Mori, M., Shiraishi, T., Fujie, T., Baba, K., Kusumoto, H., Haraguchi, M., Ueo, H., Akiyoshi, T.
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Journal Title
Dis. Colon Rectum 40
Pages: 1095-100
Description
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[Journal Article] Analysis of MT1-MMP and MMP2 expression in human gastric cancers.1997
Author(s)
Mori, M., Mimori, K., Shiraishi, T., Fujie, T., Baba, K., Kusumoto, H., Haraguchi, M., Ueo, H., Akiyoshi, T.
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Journal Title
Tnt. J. Cancer (Pred. Oncol.) 74
Pages: 316-21
Description
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[Journal Article] Microsatellite instability in Japanese colorectal carcinoma.1997
Author(s)
Nakashima, H., Mori, M., Mimori, K., Inoue, H., Baba, K., Shibuta, K., Kusumoto, H., Haraguchi, M., Ueo H., Sugimachi, K.
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Journal Title
Oncology Report 4
Pages: 387-9
Description
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[Journal Article] Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma1997
Author(s)
Tanaka, S., Mori, M., Akiyoshi, T., Tanaka, Y., Mafune, K., Wands, J. R., Sugimachi, K.
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Journal Title
Cancer Res. 57
Pages: 28-31
Description
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[Journal Article] Novel mechanism of resistance to inhibitors of DNA topoisomerases.1997
Author(s)
Beck, W. T., Khelifa, T., Kusumoto, H., Mo, Y., Rodgers, Q., Wolverton, J. S., Wang, Q.
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Journal Title
Adv. Enzyme Reg. 37
Pages: 17-26
Description
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