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ORIGINAL ARTICLES  TRENDS IN MOLECULAR DIAGNOSIS AND THERAPY OF β-THALASSEMIA AND SICKLE CELL ANEMIA


Minerva Biotecnologica 2003 June;15(2):145-51

language: English

Induction of ­fetal hemo­glo­bin by DNA-bind­ing ­drugs

Gambari R. 1, 2, Fibach E. 3

1 Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy;
2 Laboratory for the Development of Pharmacological and Pharmacogenomic Therapy of Thalassemia, Biotechnology Center, University of Ferrara, Ferrara, Italy;
3 Department of Hematology, Hadassah University Hospital, Jerusalem, Israel


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We ­here ­review ­recent pub­lished ­results show­ing ­that DNA-bind­ing ­drugs, ­such as the G+C selec­tive mith­ram­y­cin and the A+T selec­tive dis­tam­y­cin ana­logues, are ­potent induc­ers of γ-glo­bin mRNA accu­mu­la­tion and ­fetal hemo­glo­bin (HbF) pro­duc­tion in a ­human eryth­roid leu­kem­ic ­cell ­line as ­well as in cul­tures of nor­mal and thal­as­sem­ic eryth­roid pro­gen­i­tors. Erythroid pro­gen­i­tors ­derived ­from periph­er­al ­blood ­were ­grown in two-phase liq­uid cul­ture. In ­this pro­ce­dure, ear­ly eryth­roid pro­gen­i­tors pro­life­rate and dif­fer­en­tiate dur­ing ­phase I (in the ­absence of eryth­ro­poie­tin) ­into ­late pro­gen­i­tors. In ­phase II, in the pres­ence of eryth­ro­poie­tin, the lat­ter ­cells con­tin­ue ­their pro­life­ra­tion and ­mature ­into Hb-con­tain­ing ortho­chro­mat­ic nor­mo­blasts. Compounds ­were add­ed on day 4-5 of ­phase II (­when ­cells start­ed to syn­the­size Hb) and ­cells ­were har­vest­ed on day 12. Accumulation of mRNAs for γ, β- and α-glo­bins ­was meas­ured by ­real-­time quan­ti­ta­tive ­reverse tran­scrip­tion-poly­me­rase ­chain reac­tion (RT-PCR), induc­tion of HbF was ana­lyzed by ­high-pres­sure liq­uid chrom­a­tog­ra­phy (HPLC). The ­results ­obtained dem­on­strate ­that DNA-binding drugs upreg­u­late γ-glo­bin mRNA pro­duc­tion and ­increase HbF accu­mu­la­tion. These ­results are of poten­tial clin­i­cal sig­nif­i­cance as ­increase of HbF alle­vi­ates the symp­toms under­ly­ing β-tha­las­se­mia and sick­le ­cell ane­mia.

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