Enhanced fetal hemoglobin production by phenylacetate and 4- phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia

Fibach, Eitan; Prasanna, Premakala; Rodgers, Griffin P.; Samid, Dvorit

doi:10.1182/blood.v82.7.2203.2203

Cited by 91 publications

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“…Erythroid cell cultures from normal subjects. The two-phase liquid culture approach was employed as previously described (Fibach & Rachmilewitz, 1991Pope et al, 2000). Mononuclear cells were isolated from peripheral blood samples of normal donors by Ficoll-Hypaque density gradient centrifugation and seeded in alpha-minimal essential medium supplemented with 10% FBS (both from Biological Industries, Beit-Haemek, Israel), 1 mg/ml cyclosporin A (Sandoz, Basel, Switzerland) and 10% conditioned medium from the 5637 bladder carcinoma cell line.…”

Section: Dnamentioning

confidence: 99%

“…The effects of tallimustine on HbF production were studied in normal human eythroid precursor cells grown in the twostage liquid culture system as described elsewhere (Fibach & Rachmilewitz, 1991Pope et al, 2000). The mononuclear cells isolated from the buffy coat of a whole unit obtained from the blood bank were cultured in phase I (without erythropoietin) and, after 1 week, passed to phase II (with 1 unit of erythropoietin).…”

Section: Tallimustine-mediated Induction Of Hbf In Normal Human Erythmentioning

confidence: 99%

“…However, while an even modest increase in HbF levels can be clinically beneficial in sickle cell disease (Platt et al, 1991), a greater increase of HbF is necessary to reduce the severity of b-thalassaemia (Rochette et al, 1994). Accordingly, recent studies have focused on the search for compounds able to stimulate g-globin gene expression at high levels Fibach et al, 1993a;Perrine et al, 1993;Rodgers et al, 1993;Ikuta et al, 1998).…”

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confidence: 99%

“…In vitro studies demonstrate that known inducers of K562 erythroid differentiation, such as hydroxyurea, erythropoietin, butyrates and 5-azacytidine, are also capable of inducing HbF production when administered singularly or in combination with cultures of normal erythroid cells (Al-Khatti et al, 1988;Fibach et al, 1993a;Ikuta et al, 1998). In this respect, butyric acid, hydroxyurea and 5-azacytidine have been the object of recent reports focused on in vivo treatment of b-thalassaemia patients (Ley et al, 1982(Ley et al, , 1983Charache et al, 1983Charache et al, , 1992Rodgers et al, 1990Rodgers et al, , 1993Dover et al, 1992;Lowrey & Nienhuis, 1993;Perrine et al, 1993;Sher et al, 1995;.…”

mentioning

confidence: 99%

“…Apoptotic cells were identified by a colorimetric method in order to analyse possible relationships between erythroid differentiation and programmed cell death (Granville et al, 1998). Finally, the effects on HbF production were also assessed in normal erythroid progenitor cells (Fibach & Rachmilewitz, 1993;Pope et al, 2000). Cell lines and culture conditions.…”

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confidence: 99%

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Accumulation of γ‐globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine

et al. 2001

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Summary. Human leukaemic K562 cells can be induced in vitro to erythroid differentiation by a variety of chemical compounds, including haemin, butyric acid, 5-azacytidine, cytosine arabinoside, mithramycin and chromomycin, cisplatin and cisplatin analogues. Differentiation of K562 cells is associated with an increase of expression of embryofetal globin genes, such as the z-, 1-and g-globin genes. The K562 cell line has been proposed as a very useful in vitro model system to determine the therapeutic potential of new differentiating compounds as well as to study the molecular mechanism(s) regulating changes in the expression of embryonic and fetal human globin genes. Inducers of erythroid differentiation stimulating g-globin synthesis could be considered for possible use in the therapy of haematological diseases associated with a failure in the expression of normal b-globin genes. We have analysed the effects of tallimustine and distamycin on cell growth and differentiation of K562 cells. The results demonstrated that tallimustine is a potent inducer, while distamycin is a weak inducer, of K562 cell erythroid differentiation. Erythroid differentiation was associated with an increase of accumulation of g-globin mRNA and of production of both haemoglobin (Hb) Gower 1 and Hb Portland. In addition, tallimustine-mediated erythroid induction occurred in the presence of activation of the apoptotic pathway. The reasons for proposing tallimustine as an inducer of g-globin gene expression are strongly sustained by the finding that this compound stimulates fetal haemoglobin production in human erythroid precursor cells from normal subjects.

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Section: Dnamentioning

confidence: 99%

Section: Tallimustine-mediated Induction Of Hbf In Normal Human Erythmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Accumulation of γ‐globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine

et al. 2001

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BFU-E colony growth in response to hydroxyurea: Correlation between in vitro and in vivo fetal hemoglobin induction

et al. 1997

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Patients with sickle-cell anemia treated with hydroxyurea may have significant reduction in frequency and severity of pain episodes. However, previous clinical trials show a variable response to hydroxyurea. Criteria which can be used to select patients who are likely to respond to hydroxyurea treatment would be useful. Our laboratory has previously demonstrated an inverse linear relationship between the total number of burst-forming unit-erythroid (BFU-E) colonies and fetal hemoglobin levels in sickle-cell patients treated with hydroxyurea. In the present report, an in vitro cell culture system was established to evaluate the effects of hydroxyurea on BFU-E colony growth and induction of fetal hemoglobin production. Five Hb SS patients who were not previously treated with hydroxyurea and three Hb SS patients who failed to respond to hydroxyurea treatment were included in the study. The results show that the number of BFU-E colonies is decreased from 153.7 to 7.2 per 3 × 10 5 mononuclear cells, whereas fetal hemoglobin levels were increased from 5.1 to 19.4% in the presence of hydroxyurea in vitro in cultured erythroid progenitors, which were derived from 5 patients before treatment. The number of BFU-E colonies decreased from 153.7 to 2.0 per 3 × 10 5 mononuclear cells in the in vitro cultures obtained from serial peripheral blood samples over a 9-to 20-week period of oral hydroxyurea therapy. A simultaneous rise in fetal hemoglobin level from 10.2 to 28.6% in the peripheral blood over the same period of hydroxyurea therapy was also observed. Our results demonstrate that the increase in fetal hemoglobin levels in cells treated with hydroxyurea in vitro is comparable to the rise of fetal hemoglobin production following hydroxyurea therapy in these patients. On the contrary, these findings were not observed in three previously non-responsive sickle-cell patients. These results suggest that the changes in number of BFU-E colonies and fetal hemo-globin levels after in vitro exposure to hydroxyurea may be a useful approach to select sickle-cell patients who will respond to hydroxyurea therapy. Am. J. Hematol. 56:252-258, 1997.

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In vitro effect on human leukemic K562 cells of co-administration of liposome-associated retinoids and cytosine arabinoside (ara-C)

et al. 1999

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The administration of retinoids has been demonstrated to be of potential utility in the therapy of a wide spectrum of neoplastic pathologies due to the ability to induce differentiation in a large variety of primary tumor cells as well as in vitro cultured cell lines. Moreover, a number of compounds, including hemin, cytosine arabinoside, and 5-azacytidine are able to induce erythroid differentiation of the erythroleukemic cell line K562. In this paper we determined whether a combined treatment of K562 cells with suboptimal concentrations of cytosine arabinoside and retinoids containing liposomes lead to a full expression of differentiated functions. Liposomes were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters. Cell growth kinetics studies and intracellular detection of hemoglobin by benzidine staining were performed. The results obtained showed that the combined treatment with liposomes containing retinoids and sub-optimal concentration of ara-C is an effective strategy to induce K562 cell differentiation, minimizing at the same time toxic effects. Control experiments aimed to determine possible selection of subpopulations of K562 cells suggest that the observed results are not related to toxicity and/or potential selection of induced cells. In conclusion, liposomally delivered retinoids could be proposed for differentiation therapy as an effective strategy in the treatment and management of malignancy. In addition, the finding that liposomally delivered retinoids increase the capacity of cytosine arabinoside to induce erythroid differentiation, could be of interest in studies aimed at the development of treatment able to reactivate fetal globin genes in beta-thalassemia patients.

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Enhanced fetal hemoglobin production by phenylacetate and 4- phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia

Cited by 91 publications

References 0 publications

Accumulation of γ‐globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine

Accumulation of γ‐globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine

BFU-E colony growth in response to hydroxyurea: Correlation between in vitro and in vivo fetal hemoglobin induction

In vitro effect on human leukemic K562 cells of co-administration of liposome-associated retinoids and cytosine arabinoside (ara-C)

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