HEMOGLONIN PRODUCTION

THE PURPOSE OF THIS RESEARCH IS TO INVESTIGATE THE CARCINO- GENIC AND MUTAGENIC EFFECTS OF FOUR COMPOUNDS, 5-AZACYTI- DINE, HYDROXYUREA, CYTOSINE ARABINOSIDE, AND DEOXYAZACYTI- DINE, IN MICE AND RATS. THESE COMPOUNDS INDUCE THE PRODUCTION OF FETAL HEMOGLOBIN WHEN ADMINISTERED TO EITHER BABOONS OR 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 COMPOUNDSWILL BE TESTED FOR THEIR ABILITY TO CAUSE CHROMOSOMAL DAMAGEIN BONE MARROW CELLS OF RATS. ANIMALS WILL BE SACRIFICED 24HOURS FOLLOWING A DOSE ADMINISTERED BY ORAL GAVAGE. BONE MARROW CELLS WILL BE PROCESSED THROUGH HYPOTONIC AND FIXATIVE, AND CHROMOSOMAL DAMAGE WILL BE ASSESSED IN META- PHASE CELLS. IN ADDITION, THREE OF THE COMPOUNDS, HYDROXY- UREA, 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 FOR2 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 RESULTSOF THESE 14-DAY STUDIES WILL BE USED TO DETERMINE THE DOSES THAT CAN BE USED FOR SUB-CHRONIC 90-DAY STUDIES AND FOR CHRONIC 2-YEAR CARCINOGENICITY STUDIES. 5-AZACYTIDINE WILL NOT BE TESTED IN A 14-DAY STUDY DURING PHASE I, 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, SUB-CHRONIC AND CHRONIC CANCER STUDIES WILLBE PERFORMED ON THE DRUGS.