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A Probable Role for Protein Synthesis in Intestinal Epithelial Cell Damage Induced in Vivo by Cytosine Arabinoside, Nitrogen Mustard, or X-irradiation¹

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 [M. W. L., R. S. V., M. L., H. L., E. F.], and Institute of Environmental Medicine, New York University School of Medicine, New York, New York 10016 [T.-N. L., R. S.]

Cell death induced in vivo in the continuously dividing intestinal crypt epithelial cells by 1-ß-D-arabinofuranosylcytosine, nitrogen mustard, or X-irradiation can be prevented by two agents which inhibit protein synthesis: cycloheximide and tenuazonic acid. Both pretreatment and posttreatment (up to 45 min), in doses sufficient to produce an 80% drop in the rate of protein synthesis, are effective. Protection against hydroxyurea-induced cell death is similar but more variable. Our data suggest that, in this system, the active metabolic response of the cell (protein synthesis), to injurious agents, rather than mere passive attrition, is necessary for cell death. While protective to the intestinal crypt epithelium, inhibitors of protein synthesis enhance damage to lymphoid cells. It is suggested that these agents may be useful adjuncts to the X-ray and chemical treatment of lymphomas.

¹ This research was supported in part by grants from the American Cancer Society, USPHS Research Grants CA-06074 and CA-05193 (Summer Research Training Grant) from the National Cancer Institute, Grant AM-05644 from the Institute of Arthritis and Metabolic Diseases, Grants GM-135 (a training grant) and GM-10269 from the National Institutes of General Medical Sciences, and Institutional Grant IN-58H from the American Cancer Society.

² Career Development Awardee (IK04-DE35155-01) of the National Institute of Dental Research.

Received 7/16/69. Accepted 9/19/69.

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