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G Zaleskis, E Berleth, S Verstovsek, MJ Ehrke and E Mihich
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
Exposure of murine thymocytes to doxorubicin (Dox) (0.5-1.0 microM, 24 hr) triggered rapid DNA degradation, as indicated by the appearance of a major subdiploid population demonstrated by DNA flow cytometry. Electron microscopic comparison of samples with large subdiploid populations versus those with little or no such subset revealed significantly more cells with the characteristic features of apoptosis, the morphologically definable stage of programmed cell death. These features include unipolar condensed chromatin, zeiosis, and electron- dense cytoplasm. Dox-induced apoptosis occurred without prior S or G2/M phase arrest or cell size increase. The subset most susceptible to Dox- induced apoptosis in vitro and in vivo was CD3-CD4+CD8+. The same subset is affected by dexamethasone (Dex); as reported for Dex-induced apoptosis, actinomycin D and cycloheximide also blocked Dox-induced apoptosis. Thymocytes exposed to higher Dox concentrations (2-10 microM) did not have a subdiploid population. Although at 2-10 microM Dox significantly reduced cell numbers (probably as a result of necrosis), at least 5-10% of the population was viable at 24 hr. Thymocytes exposed to low concentrations of Dox (0.001-1.0 microM) plus Dex (0.1 microM) exhibited additive induction of apoptosis, whereas those exposed to high concentrations of Dox (2-10 microM) plus Dex were completely devoid of any evidence of apoptosis. These results indicate that the Dox-induced killing in thymocytes (mostly noncycling cells) occurs via different mechanisms depending upon the Dox concentration.
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