| 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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| 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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