Hematologic Toxicity of AZT and ddC Administered as Single Agents and in Combination to Rats and Mice

Hematologic Toxicity of AZT and ddC Administered as Single Agentsand in Combination to Rats and Mice. THOMPSON, M. B., DUNNICK,J. K., SUTPHIN, M. E., GILES, H. D., IRWIN, R. D., AND PREJEAN,J. D. (1991). Fundam. Appl. Toxicol. 17, 159-176. Toxicity studiesof 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine(ddC) were conducted in F344/N rats and B6C3F, mice. The drugswere administered as single agents and in combination. In allstudies, animals were treated by oral gavage twice a day, 7days a week. In studies of the individual compounds, each wasadministered for 13 weeks at the following concentrations; AZTin rats, 0, 125, 250, 500, 1000 mg/kg and in mice, 0, 25, 50,100, 400, 1000 mg/kg; ddC in rats and mice, 0, 250, 1000, 2000mg/kg. Additional male rats and female mice that were treatedwith 0, 250, 1000, or 2000 mg/kg ddC and male and female micetreated with 0, 50, 400, 1000 mg/kg AZT were maintained for30 days after treatment was stopped (at 94 days) to evaluatethe reversibility of toxic effects. Hematologic variables weremeasured on Days 5, 23, and 94 (last day of dosing), and onDay 123 (after a 30-day period without treatment). AZT and ddCproduced dose-related, poorly regenerative, macrocytic anemiasas evidenced by decreases in erythrocyte counts, he-matocrits,and hemoglobin concentrations and increases in mean corpuscularhemoglobin and mean corpuscular volume. Bone marrow samplesin rats treated with AZT were hyperplastic whereas those inmice treated with AZT and rats and mice treated with ddC werehypoplastic. The hematologic toxicity of AZT was more severethan that of ddC. Generally, toxic effects of either chemicalwere greater in mice than in rats and more pronounced in femalethan in male animals. After 30 days without dosing, hematologiceffects either resolved or dramatically improved. In studiesin which ddC and AZT were administered in combination for 4weeks at concentrations of 0/0, 0/500, 500/0, 10/500, 100/500,500/500, and 500/1000 mg/kg ddC/AZT, there was macrocytic anemiain animals in the lower doses and marked microcytic anemia insurviving male mice in higher dose groups. Most female micedied in the 500/500 and 500/1000 mg/kg ddC/ AZT dose groups.At lower concentrations (100/500, 500/1000 mg/kg ddC/AZT), effectsof the two drugs were similar to those in the single drug studies.At higher concentrations (500/500 and 500/1000 mg/kg ddC/AZT),the combination treatment produced enhanced hematopoietic toxicity.These studies demonstrated the early and progressive time courseof toxicity of AZT and ddC, species differences in sensitivitiesand responses, and reversibility of effects after terminationof treatment. Based on these findings, a chronic toxicity studyis being conducted with AZT in mice.