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Effect of Difluoromethylornithine, an Inhibitor of Polyamine Biosynthesis, on the Topoisomerase II-mediated DNA Scission Produced by 4'-(9-Acridinylamino)methanesulfon-m-anisidide in L1210 Murine Leukemia Cells¹

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205 [L. A. Z., D. K.], and Brain Tumor Research Center and the Department of Laboratory Medicine, University of California School of Medicine, San Francisco, California 94143 [L. J. M.]

Treatment of mouse leukemia L1210 cells with the polyamine biosynthesis inhibitor -difluoromethylomithine (DFMO) increased the magnitude of the DNA scission produced by the DNA intercalator 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). This enhanced DNA scission was protein concealed and protein associated, as was the m-AMSA-induced scission in cells unexposed to DFMO. The effect of DFMO required more than 6 hr to develop and was greater at 48 hr than at 24 hr of exposure to DFMO. Exogenously added putrescine partially reversed the effects of DFMO, while exerting no effect on m-AMSA-induced DNA scission in cells unexposed to DFMO. The cellular uptake of [¹⁴C]-m-AMSA was the same in DFMO-treated or untreated cells. The DNA scission and DNA-protein crosslinking produced by m-AMSA appear to represent the stabilization of an intermediate in the normal cycle of topoisomerase II function (Nelson, E. M., Tewey, K. M., and Liu, L. F., Proc. Natl. Acad. Sci. USA, 81: 1361–1365, 1984). Since polyamine depletion appears to affect the magnitude of this effect in cells, and since polyamines can alter topoisomerase II function in vitro, polyamines may be involved in topoisomerase function in vivo either directly or through secondary effects, such as alterations of the conformation of chromatin, the intracellular site at which topoisomerase acts.

¹ Supported in part by NIH Program Project Grant CA-13525.

² To whom requests for reprints should be addressed, at the Department of Chemotherapy Research, Box 52, Division of Medicine, M. D. Anderson Hospital and Tumor Institute, Houston, TX 77030.

Received 7/23/84. Accepted 12/ 7/84.