The purpose of this research is to investigate the carcinogenic and mutagenic effects of four compounds, 5-azacytidine, hydroxyurea, cytosine arabinoside, and deoxyazacytidine, in mice and rats. These compounds induce the production of fetal hemoglobin when administered to either baboons or to human patients with beta thalassemia or sickle cell anemia. As this therapy may become more widely used, it is important to determine which of these drugs has no long-term risk.During Phase I research, the four compounds will be tested for their ability to cause chromosomal damage in bone marrow cells of rats. Animals will be sacrificed 24 hours following a dose administered by oral gavage. Bone marrow cells will be processed through hypotonic and fixative, and chromosomal damage will be assessed in metaphase cells. In addition, three of the compounds, hydroxyurea, cytosine-arabinoside, and deoxyazacytidine, will be tested in 14-day toxicology studies. These three compounds will be administered to both mice and rats 5 days a week for 2 weeks. Body weight, food consumption, and clinical examination of major organs will be obtained for the high surviving dose group and the negative controls.The results of these 14-day studies will be used to determine the doses that can be used for subchronic 90-day studies and for chronic 2-year carcinogenicity studies. 5-azacytidine will not be tested in a 14-day study during Phase 1, as it has been previously tested under these conditions, and the data for selecting doses for a 2-year cancer study are available. During Phase II, subchronic and chronic cancer studies will be performed on the drugs.National Heart, Lung, and Blood Institute (NHLBI)
