Cooperative enhancement of F-cell formation in baboons treated with erythropoietin and hydroxyurea

Al-Khatti, Adil A.; Papayannopoulou, Thalia; Knitter, G; Fritsch, Edward F.; Stamatoyannopoulos, George

doi:10.1182/blood.v72.2.817.817

Cited by 43 publications

(17 citation statements)

References 16 publications

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“…However, these compounds did not give the much-needed beneficial effects to patients based on a reduction in the number and severity of painful events as the criteria for successful treatment (Ballas, 1994). A great number of other agents were also tested to find drugs that shift the oxygen dissociation equilibrium curve towards the left, increase the solubility of deoxy-Hb S, inhibit or delay the polymerization of deoxy-Hb S, induce the production of Hb F and inhibit the adhesion of RBCs to endothelial cells (Abraham & Perutz, 1986;Al-khatti et al, 1988;Ley, 1991;Perrine et al, 1993). Among the various potential antisickling agents that have been tested to date, only hydroxyurea (HU) is used for the treatment of SCD patients (Charache et al, 1992;Fibach et al, 1993).…”

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Niprisan (Nix‐0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions

2003

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Summary. The substitution of glutamic acid by valine at the sixth position of the beta-globins of haemoglobin S (Hb S) causes a drastic reduction in the solubility of the deoxy form of Hb S. Under hypoxic conditions, deoxy-Hb S molecules polymerize inside the cells, forming rigid, sickled cells. We studied the effect of Niprisan (Nix-0699), a naturally occurring antisickling agent, on the survival of transgenic (Tg) sickle mice under severe acute hypoxic conditions (60 min). Before hypoxia exposure, the mice were treated by gavage once daily for 7 d with 0 mg/kg (n ¼ 10), 10 mg/kg (n ¼ 5), 50 mg/kg (n ¼ 5), 300 mg/kg (n ¼ 4) or 500 mg/kg (n ¼ 5) of Nix-0699. The mean survival times of the untreated and treated mice were 10, 25, 39, 55 or 60 min respectively. The percentage of sickled cells in the venous blood of the treated mice was lower than that in control mice and was dose dependent. Histological examination of the lungs of the control mice showed entrapment of massive numbers of sickled cells in the alveolar capillaries, although the degree of such entrapment decreased with the increased dose of Nix-0699. Nix-0699 may be a promising option for the treatment and management of patients with sickle cell disease.

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confidence: 99%

Niprisan (Nix‐0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions

2003

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“…The above approaches did not give the much-needed beneficial effects based on the reduction of painful crises as the criterion for successful treatment (Ballas, 1994). Furthermore, several other agents were tested to find drugs that shift the oxygen-dissociation curve (ODC) towards the left, increase the solubility of deoxy-Hb S, inhibit or delay the polymerization of deoxy-Hb S, induce the production of Hb F, and inhibit the adhesion of red blood cells to endothelial cells (Abraham & Perutz, 1986;Al-khatti et al, 1988;Ley, 1991;Perrine et al, 1993). Among the compounds tested, hydroxyurea (HU) is the only agent currently in clinical use for the management and treatment of SCD (Charache et al, 1992;Fibach et al, 1993).…”

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In vitro effects of NIPRISAN (Nix‐0699): a naturally occurring, potent antisickling agent

2002

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Summary. Among the various potential antisickling agents tested, hydroxyurea (HU) has been the most effective compound used for the treatment of patients with sickle cell disease (SCD). Although HU is effective in many patients, not all patients respond to this drug. In addition, some patients reveal adverse effects, including myelosuppression. In an attempt to find other effective agents with less adverse effects, we investigated the antisickling effect of NIPRISAN (Nix-0699). We found that Nix-0699, an ethanol/water extract from indigenous plants, has a strong antisickling effect. The concentration of Nix-0699 required to inhibit 50% of erythrocyte sickling was about 0AE05 mg/ml. As for the kinetics of polymerization, addition of 0AE05 lg/ml Nix-0699 caused a sixfold prolongation of the delay time prior to deoxy-Hb S polymerization when compared with that of untreated Hb S samples. The solubility of deoxy-Hb S significantly increased upon treatment with Nix-0699. Analysis of the effect of Nix-0699 on the Hb S oxygen affinity indicated that the drug slightly shifted the oxygendissociation curve of Hb S toward the left without any apparent change in the Hill coefficient. These results suggest that the antisickling properties of Nix-0699 may involve direct interaction with Hb molecules. Incubation of red blood cell (RBC) suspensions with various concentrations of Nix-0699 did not dehydrate RBCs, cause haemolysis, increase the amount of denatured Hb, nor form met-Hb. In view of the outcome of this study, Nix-0699 may be a promising option for the treatment of patients with SCD.

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“…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;.…”

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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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Cooperative enhancement of F-cell formation in baboons treated with erythropoietin and hydroxyurea

Cited by 43 publications

References 16 publications

Niprisan (Nix‐0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions

Niprisan (Nix‐0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions

In vitro effects of NIPRISAN (Nix‐0699): a naturally occurring, potent antisickling agent

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

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