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Enhanced Expression of DNA Topoisomerase II by Recombinant Human Granulocyte Colony-stimulating Factor in Human Leukemia Cells¹

First Department of Internal Medicine, Nagoya University School of Medicine [M. T., Y. I., Y. M., M. T., K. K., Y. M., H. S.] Showa-ku, Nagoya 466, and Department of Biochemistry, Aichi Cancer Center Research Institute [T. A.], Chikusa-ku, Nagoya 464, Japan

The effect of recombinant human granulocyte colony-stimulating factor (G-CSF) on DNA topoisomerase II (topo II) expression was studied in two human acute myelogenous leukemia cell lines, NKM-1 and NOMO-1, which express G-CSF receptor and proliferate in response to exogenous G-CSF. Northern blot analysis revealed that the level of topo II mRNA in 16-h stimulated cells in serum-free medium with G-CSF (10 ng/ml) was approximately 2-fold higher than that in cells without G-CSF. Enhanced topo II mRNA expression was detectable within 3 h after the addition of G-CSF. Topo II activity in crude nuclear extracts from 16-h G-CSF-stimulated cells was also found to be approximately 2-fold greater than that from unstimulated cells. According to in vitro cytotoxic assay, the sensitivity of G-CSF-stimulated cells to intercalating (daunorubicin) and nonintercalating (etoposide) topo II-targeting drugs increased significantly, whereas no enhancement of sensitivity was observed with an alkylating agent (4-hydroperoxycyclophosphamide). The augmented drug sensitivity observed was not due to the increased level of drug transport, as suggested by the similar extent of [³H]etoposide uptake between G-CSF-stimulated and unstimulated and unstimulated cells. By measuring the topo II mRNA and the cytotoxicity of the above mentioned drugs, we obtained essentially the same results in G-CSF-responsive leukemia cells isolated from three acute myeloblastic leukemia patients, as observed in the cultured cell lines. These findings strongly suggest that the sensitivity to "topo II-targeting drugs" could be augmented by exogenous G-CSF through elevated topo II activity in G-CSF-responsive leukemia cells.

¹ This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture; a Grant-in-Aid from the Ministry of Health and Welfare; and a Grant-in-Aid from the Aichi Blood Disease Research Juridical Foundation in Japan.

² To whom requests for reprints should be addressed, at First Department of Internal Medicine, University School of Medicine, 65 Tsurumaicho, Nagoya 466, Japan.

Received 5/29/90. Accepted 8/ 8/90.

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