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 The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009.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.
3'-Azido-3'-deoxythymidine (AZT) is presently being used successfully for the treatment of HIV positive individuals and is also used for the treatment of AIDS patients. Currently, AZT is considered by some as a standard treatment to prevent maternal transmission of the AIDS virus by treating the mother in the last weeks of pregnancy and continuing treatment with the baby. Previous studies by Luster et al.1 showed that some of the anti-HIV drugs had adverse effects on the immune system. Cao et al.2 showed the B lymphocyte was a target for the 2',3' dideoxyadenosine. Because of the long duration of treatment of humans, a six-month daily dosing study of AZT was recommended by the Food and Drug Administration.
3'-Azido-3'-deoxythymidine was nominated to the NTP for toxicological evaluation and was selected for immunotoxicity studies by the chemical manager. Thus, the purpose of these studies was to determine the potential effects of 3'-azido-3'-deoxythymidine on the immune system.
The studies were conducted in female B6C3F1 mice. The animals were treated daily for 180 days by oral gavage. The in-life phase of the study was conducted between September 26, 1996 and May 7, 1997. AZT was prepared weekly as a solution in Maalox Therapeutic Concentrate (T.C.).
The baseline toxicology studies are summarized in Table ES-1. Oral administration of AZT at 50, 125, 250 and 500 mg/kg/day for 180 days significantly decreased body weight and rate of weight gain at the 500 mg/kg dose level when the 5 studies are combined. A significant dose-dependent increase in relative spleen weight was seen, reaching 31% at the 500 mg/kg dose. These studies confirmed the significant decreases in the erythroid elements seen in other animal and clinical studies. These significant effects were observed at all dose levels for erythrocyte number (28%), hemoglobin (10%), mean corpuscular volume (30%), mean corpuscular hemoglobin (24%) and mean corpuscular hemoglobin concentration (4%) resulting in a NOAEL with these parameters of below 50 mg/kg. The percent reticulocytes were significantly increased at all dose levels from 20% to 95%. The leukocyte number was significantly decreased only at the high dose by 21%. In evaluating the bone marrow, no alteration was seen in the CFU-E (colony-forming units-erythrocytes); however, there were increases in CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage).
Table ES-2 summarizes the immunology studies. In the immune parameters evaluated, no alteration was seen in the T-dependent antibody-forming cell response to s-RBC; however, a significant decrease was observed with the serum IgM antibody titer up to 16%. When expressed as lytic units per spleen, the cytotoxic T lymphocyte cell response showed a significant dose-dependent decrease up to 66%. Significant high dose decreases were also observed in the natural killer cell number and in the number of CD4+ spleen cells.
In conclusion, adverse toxicological effects are present in mice treated with AZT for 180 days as seen in a decrease of body weight at the high dose and a significant decrease in the erythroid elements at all doses. Increases were seen in the CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage). Adverse immunotoxicological effects are present in mice treated with AZT for 180 days as seen in a decrease in the serum sRBC titer, cytotoxic T lymphocyte response, and absolute T helper cells and NK cells, resulting in NOAEL of below 125 mg/kg, 50 mg/kg and 250 mg/kg, respectively. Information on these immune alterations could be beneficial when using AZT in the treatment of AIDS patients.