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Cytostatic and Cytotoxic Effects of Fostriecin on Human Promyelocytic HL-60 and Lymphocytic MOLT-4 Leukemic Cells¹

The Cancer Research Institute, New York Medical College, Valhalla, New York 10595

Exposure of exponentially growing human promyelocytic or lymphocytic leukemic cells to the putative DNA topoisomerase II inhibitor fostriecin (FST), at a concentration of 1 µM, results in the suppression of their rate of progression through the S and G₂ phases of the cell cycle. At concentrations between 5 µM and 0.5 mM, FST triggers endonucleolytic DNA degradation in human promyelocytic leukemia cells, resulting in apoptotic cell death; this effect is not selective for any particular phase of the cell cycle. Little or no apoptotic cell death is observed in lymphocytic leukemic cells at any FST concentration. Because FST, unlike other inhibitors of topoisomerase II, such as teniposide (TN) or amsacrine (m-AMSA), does not stabilize cleavable DNA-topoisomerase complexes, the observed differences between the effects of FST versus TN or m-AMSA on the cell cycle may provide clues regarding the role of such complexes in the kinetic effects of these inhibitors. The present results, therefore, are compared with our earlier data on the effects of TN and m-AMSA on the same cells. The only observed difference is the loss of cell cycle phase-specific triggering of DNA degradation by FST in human promyelocytic leukemia cells, compared to the S phase-specific effects of TN and m-AMSA. Therefore, stabilization of the DNA-topoisomerase cleavable complexes may be essential in the selectivity of cell kill during S phase. However, it appears that the presence of stabilized complexes is not essential to the suppression of cell progression through S or G₂ or the induction of apoptotis or necrosis, in general, by topoisomerase II inhibitors.

¹ Supported by USPHS Grants R37 CA23296 and CA28704 and the Carl Inserra Fund. M. A. H. is supported by Margarete und Walther Lichtenstein-Frank-Stiftung, G. D. B. was supported by a fellowship from Istituto Nazionale per lo Studio e la Cura dei Tumori.

² To whom requests for reprints should be addressed, at The Cancer Research Institute, New York Medical College, 100 Grasslands Road, Elmsford, NY 10523.

Received 6/28/91. Accepted 1/ 9/92.