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The Nature of Adriamycin-induced Cytotoxicity in Chinese Hamster Cells as Revealed by Premature Chromosome Condensation¹

Department of Developmental Therapeutics, The University of Texas at Houston, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77025

The short- and long-term effects of adriamycin treatment on the cell cycle kinetics and chromosome structure of Chinese hamster ovary cells were investigated. Adriamycin treatment, either pulse or continuous, did not delay the progression of G₁ cells into S phase but did prolong the duration of S and G₂ phases. This effect was dose dependent, and the prolongation of G₂ period was greater than that of S. The frequency of chromosomal aberrations induced by adriamycin was studied in the mitotic as well as in the prematurely condensed chromosomes (PCC) of the treated cells. The types of aberrations observed were chromosome stickiness, chromatid exchanges, breaks, and gaps. The frequency of aberrations continued to increase as cells progressed to mitosis even after the removal of drug from the medium. At prolonged intervals (24 to 72 hr) after a brief or extended treatment, the labeling indices of the treated populations decreased, indicating an eventual block in the cell cycle progression. Visualization of chromosomes of these blocked interphase cells by the PCC method revealed that normal G₂ PCC were totally absent. We observed that the PCC of these blocked cells were abnormal in the following respects: (a) some of the G₂ PCC were extensively damaged; (b) many of the S PCC failed to incorporate [³H]thymidine; (c) a significant fraction of these PCC were poorly condensed and hence it was difficult to determine whether they were in G₁ or G₂. These results indicate that there is a good correlation between damage to the genome and the inhibition of cell cycle progression after adriamycin treatment.

¹ This investigation was supported in part by Grants CA-16480 and CA-14528-02 and Contract NO1-CM-61156 from the National Cancer Institute, NIH, USPHS, and Grant VC-163 from the American Cancer Society.

Received 4/14/75. Accepted 7/25/75.

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