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 cells.
Short-term (2-6 h) exposure of human promyelocytic HL-60 cell cultures to the DNA topoisomerase I inhibitor camptothecin (0.05-0.5 microgram/ml) or to the topoisomerase II inhibitor, teniposide (VM-26; 0.3-3.0 micrograms/ml) or 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine; 0.8 microgram/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 microgram/ml) or doxorubicin (adriamycin; 0.4-10.0 micrograms/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.
Del Bino
G
G
Cancer Research Institute, New York Medical College, Valhalla 10595.
Darzynkiewicz
Z
Z
D000677:Amsacrine / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008942:Mitoxantrone / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D013713:Teniposide / Q000494:pharmacology*
D000677:Amsacrine; D004317:Doxorubicin; D004247:DNA; D013713:Teniposide; D008942:Mitoxantrone; D002166:Camptothecin