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Toxicity Studies in Mice Treated with 1-ß-D-Arabinofuranosyl-cytosine (ara-C)¹

Department of Pathology, University of Alabama Medical Center, Birmingham, Alabama 35233

Optimum therapeutic dosage schedules of 1-ß-D-arabinofuranosylcytosine (ara-C) administered intraperitoneally in mice (15 mg/kg/dose, every 3 hours for 24 hours) result in karyorrhectic damage to the crypt epithelial cells of the intestinal mucosa. This damage is most severe at 4 hours (earliest observations made) following conclusion of the 24-hour course, after which there is a rapid recovery to completion in 72 hours. The damage is thus transitory and resembles that of hydroxyurea. This cycle of transitory intestinal damage followed by recovery occurs after each therapeutic dosage schedule of ara-C as long as the schedule is not repeated more often than every 4th day.

Progressive damage to the intestinal mucosa accompanied by changes in the hematopoietic tissues occurs only if this optimum therapeutic dose (15 mg/kg/dose, every 3 hours) is continued uninterrupted to the LD₁₀₀ dose (360 mg/kg in 72 hours) and beyond. Irreversible changes are seen in the intestinal mucosa, and a progressive depopulation of the bone marrow with ultimate aplasia ensues as the LD₁₀₀ dose is reached and surpassed.

¹ The part of the work carried out at Southern Research Institute was supported by the Cancer Chemotherapy National Service Center of the National Cancer Institute, under Contract No. PH43-65-594.

² Kettering-Mayer Laboratory, affiliated with Sloan-Kettering Institute, Southern Research Institute, Birmingham, Alabama.

Received 7/29/68. Accepted 11/ 1/68.

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