Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice

Meiler, Steffen E.; Wade, Marlene; Kutlar, Ferdane; Yerigenahally, Shobha; Xue, Yongjun; Parseval, Laure A Moutouh-de; Corral, Laura G.; Swerdlow, Paul; Kutlar, Abdullah

doi:10.1182/blood-2010-11-319137

Cited by 73 publications

(58 citation statements)

References 18 publications

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“…With regarding to bone marrow smears, there was significant increase in M/E ratio in all treated groups along the period of experiment except HU 250 group which did not show any significant change in the first and second period of experiment. This result agree with Meiler et al (2011) who reported increase in M/E ratio induced by hydroxyurea in mice injected 100 mg/kg intraperitoneally daily for 8 weeks. Moreover, all the bone marrow smears showed hypocellularity, reduction of myeloid and erythroid series and decrease in megakaryocytes.…”

Section: Discussionsupporting

confidence: 82%

“…These findings came in accordance with Card et al (1968) who reported depression of erythropoiesis and hypoplasia of the bone marrow in rabbits injected intraperitoneally by hydroxyurea 100 or 200 mg/kg/day for 8 days. Also, our findings agreed with Meiler et al (2011). These results could be attributed to formation of nitric oxide that metabolized from HU (Yarbro, 1992;Koviac, 2011) and Hydroxyurea also inhibits the incorporation of thymidine into DNA and may directly damage DNA causing diminution in cellular proliferation in the marrow (Krakoff et al, 1968;Yarbro, 1992).…”

Section: Discussionsupporting

confidence: 81%

“…Additionally, severe methaemoglobinaemia in dogs (Wray, 2007) and cats (Plumb, 2005) associated with HU toxicity was reported. Hypocellularity in bone marrow and increased M/E ratio in relation to usage of HU was previously reported in mice (Meiler et al, 2011). Moreover, Card et al (1968 concluded depression of erythropoiesis and hypoplasia of bone marrow smear in rabbits treated with hydroxyurea.…”

Section: Introductionmentioning

confidence: 95%

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Hematocytological Evaluation of Hydroxyurea-Induced Toxicity in Male Rats

Khamis¹,

Oda²,

Khafaga³

et al. 2017

AJVS

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Key words:hydroxyurea, bone marrow, aplastic anemia, hematology.The toxicity of hydroxyurea (HU), a treatment for specific neoplasms, sickle-cell disease, polycythemia vera and thrombocytosis was assessed in rats. Forty rats were divided equally into four groups. The first group was kept as control and received only purified water, the second group (HU250) orally administered hydroxyurea 250 mg/kg b.wt/day, the third group (HU500) administered hydroxyurea 500 mg/kg b.wt/day and the fourth group (HU750) administered hydroxyurea 750 mg/kg b.wt/day. The treatment was continued for 20 days. The evaluated parameters were assessed after 10 and 20 days of the experiment. Results revealed decrease in body weight in all treated groups. In addition, decreased circulating leukocytes, erythrocytes and platelets with decreased bone marrow cellularity were evident in all treated groups with different degree of severity. Moreover, aplastic anemia associated with marked severe hypocellularity of bone marrow was detected in HU500 and HU750 groups on the second period of the experiment. It could be concluded that hydroxyurea administration induced hematopoietic and bone marrow toxicity in rats.Correspondence to:

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Hematocytological Evaluation of Hydroxyurea-Induced Toxicity in Male Rats

Khamis¹,

Oda²,

Khafaga³

et al. 2017

AJVS

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“…The combination of HU with pomalidomide was more effective that its combination with lenalidomide [62]. In vivo studies of these two agents in transgenic animals have shown increased HbF expression, without any myelosuppressive effect, at levels similar to those in the HU-treated controls [63]. …”

Section: Induction Of Hbf Synthesismentioning

confidence: 93%

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Melo¹,

Ercolin²,

Chelucci³

et al. 2015

Inherited Hemoglobin Disorders

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Sickle cell disease (SCD) is one of the most common genetic disorders worldwide. It is caused by a point mutation that changes glutamic acid (Glu6) to valine (Val6) in the β chain of hemoglobin. Vaso-occlusion is the most well-known problem associated with SCD. Despite recent advances in understanding the disease at the molecular level, few therapeutic strategies are available. Hydroxyurea is the only drug currently approved by the U.S. Food and Drug Administration for the disease, and it has serious adverse effects and lack of efficacy in some patients. However, new therapeutic approaches are under investigation in the hope of discovering new drugs to treat SCD.These include agents that: a) increase nitric oxide bioavailability; b) modify the rheological properties of the blood; c) bind covalently to hemoglobin; d) prevent hemoglobin dehydration; e) reduce iron overload; and f) induce the expression of gamma globin and fetal hemoglobin. In this chapter, we discuss the current treatment of SCD and the advances made in medicinal chemistry to find new drugs to treat this neglected hematological disease.

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“…Surprisingly, pomalidomide improved erythropoiesis in comparison to myelosuppresion seen with HU. However, when given in combination with HU, this effect was lost and fetal Hb levels were suppressed [50]. A phase I study of pomalidomide in SCD was completed.…”

Section: Fetal Hemoglobin Inducing Agentsmentioning

confidence: 99%