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The Cell Cycle Related Differences in Susceptibility of HL-60 Cells to Apoptosis Induced by Various Antitumor Agents¹

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

The studies were aimed to detect the cell cycle-associated differences in the susceptibility of HL-60 cells to apoptosis induced by diverse agents. Exponentially growing HL-60 cells were treated with the DNA topoisomerase I inhibitor camptothecin; the DNA topoisomerase II inhibitors teniposide, m-AMSA, Mitoxantrone, or Fostriecin; the presumed tyrosine kinase inhibitor genistein; a serine/threonine kinase inhibitor H7; the protein synthesis inhibitor cycloheximide; the DNA replication inhibitor hydroxyurea; the nucleoside antimetabolites 1-ß-D-arabinofuranosylcytosine and 5-azacytidine; and the alkylating agent nitrogen mustard, cisplatin, hyperthermia, and irradiation. Endonucleolysis, which accompanied apoptosis induced by these agents, was assessed by two different flow cytometric methods, one based on DNA content measurements following extraction of low molecular weight DNA, and another using exogenous terminal deoxynucleotidyl transferase to label in situ DNA strand breaks. Each method allowed for both identification of apoptotic cells and analysis of the cell cycle distribution of the unaffected cell population; the method using terminal transferase also allowed for identification of the cell cycle position of apoptotic cells. Confirmed by analysis of DNA degradation by gel electrophoresis and changes in cell morphology, apoptosis was observed as early as 3 h after administration of most drugs and for some drugs was cell cycle phase specific. Cells progressing through S phase were selectively susceptible when treated with camptothecin, teniposide, m-AMSA, Mitoxantrone, H7, hydroxyurea, and 1-ß-D-arabinofuranosylcytosine. Cells in G₂-M preferentially underwent apotosis in cultures treated with H7 or with -irradiation. Cells in G₁ phase were preferentially affected by 5-azacytidine, nitrogen mustard, and hyperthermia. No significant cell cycle specificity was observed in the case of Fostriecin, genistein, cycloheximide, or cisplain. The cell cycle related difference in susceptibility to apoptosis may be a reflection of both the severity of the lesion induced by a given drug and the ability of the cells to repair that lesion; both can vary depending on the cell cycle phase.

¹ This work was supported by USPHS Grant RO1 CA28704 as well as the Carl Inserra Fund and the Dr. I Fund Foundation. W. G. is a fellow of the Alfred Jurzykowski Foundation, on leave from the Department of Tumor Pathology, Medical Academy of Szczecin, Poland. J. G. is an awardee of the fellowship established by "This Close" for Cancer Research, Inc. Foundation.

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

Received 2/12/93. Accepted 4/28/93.

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