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Camptothecin, Teniposide, or 4'-(9-Acridinylamino)-3-methanesulfon-m-anisidide, but not Mitoxantrone or Doxorubicin, Induces Degradation of Nuclear DNA in the S Phase of HL-60 Cells¹

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

Short-term (2–6 h) exposure of human promyelocytic HL-60 cell cultures to the DNA topoisomerase I inhibitor camptothecin (0.05–0.5 µg/ml) or to the topoisomerase II inhibitor, teniposide (VM-26; 0.3–3.0 µg/ml) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine; 0.8 µg/ml) triggered rapid degradation of DNA specifically in S-phase cells. As a result of the selective death of S-phase cells, only G₁ cells remained in these cultures. On the other hand, mitoxantrone (0.02–0.4 µg/ml) or doxorubicin (adriamycin; 0.4–10.0 µg/ml) did not induce DNA degradation in S phase but arrested HL-60 cells in S and G₂ phases. In contrast to HL-60 cells, human lymphocytic leukemic MOLT-4 cells responded to all of these drugs (camptothecin, teniposide, amsacrine, mitoxantrone, and adriamycin) at all concentrations tested, invariably by being arrested in G₂ and S phases and also by entering a higher DNA ploidy cycle. The data illustrate the differences in the sensitivity of S-phase cells in myelogenous versus lymphocytic leukemic lines to both DNA topoisomerase I and II inhibitors and emphasize the tissue (leukemia type)-specific factors that modulate the cytostatic and cytotoxic effects of these inhibitors. The qualitatively different response of HL-60 cells to camptothecin, teniposide, or amsacrine (by rapidly triggered DNA degradation in S phase) as compared to mitoxantrone or adriamycin (by cell arrest in G₂ and S) suggests that, despite the generally assumed common mode of action attributed to these drugs (i.e., via stabilization of the cleavable DNA-topoisomerase complexes), there are significant differences in the mechanisms by which they exert cytostatic/cytotoxic effects.

¹ Supported by National Cancer Institute Grants R37 CA23296 and RO1 CA28704. G. D. B. was supported by a fellowship from the Istituto Nazionale per lo Studio a la cura dei Tumori and in part by the Associazione Italiana per la Ricerca sul Cancro, Milano, Italy.

² To whom requests for reprints should be addressed.

Received 11/12/90. Accepted 12/ 3/90.

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