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Effect of Polyamine Depletion by -Difluoromethylornithine or (2R,5R)-6-Heptyne-2,5-diamine on Drug-induced Topoisomerase II-mediated DNA Cleavage and Cytotoxicity in Human and Murine Leukemia Cells¹

Departments of Medical Oncology [M. B., D. C., L. A. Z.] and Hematology [E. J. F.], Division of Medicine, The University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030, and the Brain Tumor Research Center and the Department of Laboratory Medicine, University of California School of Medicine, San Francisco, California 94143 [L. J. M.]

The effects of -difluoromethylornithine (DFMO), an ornithine analogue which is an ornithine decarboxylase inhibitor, on the actions of the topoisomerase II-reactive agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide (VP-16) were investigated in 2 murine L1210 leukemia lines and 2 human HL-60 leukemia lines. One of the human lines was resistant to the cytotoxic and DNA cleaving effects of m-AMSA (HL-60/AMSA). In all 4 lines, -DFMO depleted cellular putrescine and spermidine to nondetectable levels. VP-16-induced DNA cleavage (quantified using alkaline elution) was decreased in all lines following -DFMO treatment. The m-AMSA-induced DNA cleavage was decreased in one of the L1210 lines and in the HL-60 line sensitive to m-AMSA; m-AMSA-induced DNA cleavage was increased in the other L1210 line. The low frequency of m-AMSA-induced DNA cleavage produced in HL-60/AMSA was unaffected by -DFMO treatment. Alterations in drug-mediated DNA effects induced by -DFMO could not be uniformly explained by -DFMO-induced alterations in m-AMSA or VP-16 cellular uptake, as indicated by direct measurements of cell-associated drug or results of DNA cleavage assays in nuclei isolated from -DFMO-treated cells. Exogenous putrescine prevented the effects of -DFMO on drug-induced DNA cleavage, substantiating polyamine depletion as the cause of the altered frequency of DNA cleavage. Cytotoxicity assays in 2 of the lines demonstrated that drug-induced reductions in colony-forming ability paralleled drug-induced DNA cleavage. (2R,5R)-6-heptyne-2,5-diamine, a putrescine analogue which is also an ornithine decarboxylase inhibitor, was also used to deplete polyamine levels in HL-60. (2R,5R)-6-heptyne-2,5-diamine was more potent than -DFMO and produced effects on m-AMSA- and VP-16-induced DNA cleavage and cytotoxicity identical to those produced by -DFMO.

¹ Supported by PHS Grants CA40090 (L. A. Z.), CA39809 (E. J. F.), and Program Project Grant CA13525 (L. J. M.), by Grant CH-324 (L. A. Z.) from the American Cancer Society, and by a gift to the M. D. Anderson Annual Fund for the Chemotherapy Research Program by Mr. Henry C. Beck, Jr., of Dallas, Texas.

² Visiting scientist from the Internal Clinic of Medical Faculty, University of Nis, Yugoslavia.

³ To whom requests for reprints should be addressed, at Box 52, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 3/18/87. Revised 8/17/87. Accepted 9/22/87.