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Laboratory of Biochemistry [R. I., T. M., T. A.], Laboratory of Ultrastructure Research [K. R. U.] and Biophysics Unit [K. T.], Aichi Cancer Center Research Institute, Chikusa-Ku, Nagoya 464; and Research Laboratory, Zenyaku Kogyo Co., Ltd. 33-7 Ohizumi-machi 2-chome Nerima-Ku, Tokyo, Japan [T. N., R. Y., M. S.]
In the accompanying paper (K. Tanabe, Y. Ikegami, R. Ishida, and T. Andoh, Cancer Res., 51: 4903–4908, 1991), we showed that ICRF-154 and -193, dioxopiperazine derivatives, inhibited the activity of purified topoisomerase II, without formation of a cleavable DNA-protein complex. In order to see whether ICRF-154 and ICRF-193 affect cellular topoisomerase II in situ or not, we examined the effect of these drugs on etoposide (VP-16)-induced, topoisomerase II-mediated DNA breaks in RPMI 8402 cells by alkaline sedimentation analysis. When RPMI 8402 cells were exposed to VP-16 in the presence of ICRF-154 or ICRF-193 for 1 h, VP-16-induced DNA strand breaks were greatly inhibited by both ICRF compounds. In parallel with this observation, VP-16-induced growth inhibition was also reversed by ICRF-193. Exposure of cells to ICRF-154 resulted in a progressive accumulation of cells with 4C DNA content. Although mitotic index did not significantly increase, mitotic abnormalities were seen in cells exposed to ICRF-193 or ICRF-154: all mitotic cells exhibited early mitotic figures with fewer condensed and entangled chromosomes. The most sensitive phase of the cell cycle to ICRF-154 was the G2-M. ICRF-154 did not affect the spindle formation. However, abnormally oriented spindles were observed in drug-treated cells in parallel with the appearance of multinucleated cells. The results suggest that ICRF-154 and -193 inhibit topoisomerase II activity in RPMI 8402 cells, and this effect resulted in the appearance of cells in G2 and early M phase with fewer condensed and entangled chromosomes and of cells with multilobed nuclei.
1 This work was supported in part by Grants-in-Aid for the Cancer Research from the Ministry of Education, Science, and Culture, and the Ministry of Health and Welfare of Japan.
2 To whom requests for reprints should be addressed.
Received 4/ 2/91. Accepted 7/ 9/91.
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