The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.
The nucleoside analog, 2'3'-dideoxydidehydrothymidine (D4T), has been shown to be a potent inhibitor of HIV replication in vitro. Clinical trials are being conducted to determine its efficacy in human subjects. This study was undertaken to assess the immunotoxicity and myelotoxicity of D4T in C57BL/6 and DBA/2 mice.
D4T, lot number R060190/05, was obtained from the Raylo Chemical Co. and was determined to be ~98% pure by HPLC. D4T was dissolved in distilled water and administered at dose levels of 125, 250, and 500 mg/kg in both C57BL/6 and DBA/2 female mice. Thirty mice were used in each of the five test groups (control, three dosed groups, and a positive control) with 10 mice per group. With the exception of mice immunized with sheep red blood cells, all positive control mice were dosed i.p. with 100 mg/kg cyclophosphamide (CTX, Sigma Chemical Company, St. Louis, MO), at a volume of 0.1 ml per 10 gm body weight, two days prior to sacrifice. D4T treated mice were dosed daily by oral gavage with a volume of 0.1 ml per 10 g of body weight, 7 days/week, for 30 days.
General toxicological data and immunology data are summarized in Tables 1 and 2 for the two mouse strains. The immunotoxicological effects of this compound were negligible. No dose-related mortality, body weight changes, or gross lesions were observed. All groups of C57BL/6 mice showed normal weight gain over the 30- day period, although DBA/2 mice showed minimal weight gain. There were no significant differences between any of the treatment groups in body weight. Dose-related increases in spleen and liver weights were observed. For boths strains of mice, erythropenia and depressed hematocrits were seen at highest dose. No other hematological parameter was modulated by D4T. There were no D4T- related effects in any of the cell-mediated or humoral immune function assays. Significant decreases in both nucleated cells per femur and CFU-E's were seen with the C57BL/6 mice but not the DBA/2 mice.
Under these experimental conditions, treatment with D4T for 30 days produced no significant effects on cell-mediated immunity, humoral immunity or NK cell activity. However, there was significant hematotoxicity and myelotoxity as measured by nucleated cells per femur, CFU-E, and RBC counts. Based upon these findings it is likely that the observed effects on peripheral RBC was a manifestation of D4T induced suppression of erythropoiesis.