Transgenic mouse model of pharmacologic induction of fetal hemoglobin: studies using a new ribonucleotide reductase inhibitor, Didox.
Evaluation of pharmacologic agents that stimulate fetal hemoglobin production has been done mainly in baboons and macaques. We investigated whether results in transgenic mice can predict the stimulation of fetal hemoglobin in primates, by testing gamma globin induction in response to a new ribonucleotide reductase inhibitor, Didox. A transgenic mouse line carrying the human A gamma gene linked to a locus control region cassette was used. Treatment of transgenic mice with Didox resulted in induction of gamma gene expression as documented by an increase in F reticulocytes and F cells and an elevation of gamma/gamma + beta biosynthetic ratio. Similarly, administration of Didox to a baboon in the nonanemic and chronically anemic state resulted in induction of gamma gene expression as shown by increases in F reticulocytes, F cells, and Hb F. These results suggest that the muLCR-A gamma transgenic mice can be used to screen new pharmacologic compounds for gamma globin inducibility.
Pace
B S
BS
Department of Medicine, University of Washington, Seattle.
Elford
H L
HL
Stamatoyannopoulos
G
G
D000740:Anemia / Q000139:chemically induced; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004921:Erythropoietin / Q000627:therapeutic use; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000627:therapeutic use; D012156:Reticulocytes / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013921:Thrombocytopenia / Q000139:chemically induced
D006877:Hydroxamic Acids; D011994:Recombinant Proteins; D004921:Erythropoietin; D005319:Fetal Hemoglobin; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid