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Relationship of DNA Topoisomerase II and ß Expression to Cytotoxicity of Antineoplastic Agents in Human Acute Lymphoblastic Leukemia Cell Lines¹

Department of Pharmacology [G. A. B., J. P. M., L. G., R. T., K. L. D., G. J. G.], Medicine [D. W. H., G. J. G.], and Pediatrics [M. H. F.] and the Interdepartmental Division of Oncology [D. W. H., G. J. G.], University of Toronto, Toronto, Ontario, M5G 1L4; Department of Medicine and Pathology, Ontario Cancer Institute, Toronto, Ontario, M4X 1K9 [D. W. H.]; and the Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8 [M. H. F.], Canada

The levels of expression of topoisomerase II and topoisomerase IIß were investigated in six established cell lines of human childhood acute lymphoblastic leukemia (ALL) as a function of doubling time, cell cycle distribution, and of sensitivity to the antineoplastic agents Adriamycin and etoposide. The slowest growing cell line, ALL-G, was most sensitive to both drugs, whereas the fastest growing cell line, ALL-C, was 15.3- and 6.4-fold more resistant than ALL-G to Adriamycin and etoposide, respectively. Furthermore, ALL-W, the second most rapidly dividing cell line, was most resistant to both Adriamycin (22.8-fold) and etoposide (14.1-fold). Expression of topoisomerase II varied inversely with doubling time, whereas no correlation was found between topoisomerase IIß levels and doubling time. Expression of topoisomerase IIß varied inversely with that of topoisomerase II. The level of topoisomerase II correlated directly with the percentage of cells in S and G₂-M phases, whereas topoisomerase IIß expression varied directly with the number of cells in G₁. An inverse correlation was found between the level of expression of topoisomerase IIß and resistance to Adriamycin, whereas a direct correlation was observed between the level of expression of topoisomerase II and resistance to Adriamycin. Studies with etoposide, although not statistically significant, were consistent with the pattern observed with Adriamycin. These findings suggest that in ALL cells, cytocidal activity of Adriamycin and etoposide may be mediated, at least in part, by topoisomerase IIß.

¹ This research was supported by an operating grant from the Leukemia Research Fund of Canada and by Grants 4008 and 4518 from the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed, at the Interdepartmental Division of Oncology, University of Toronto, 92 College Street, Toronto, Ontario M5G 1L4, Canada.

Received 7/ 6/94. Accepted 10/31/94.

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