Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications

Kovacic, Peter

doi:10.1016/j.mehy.2010.08.023

Cited by 47 publications

(44 citation statements)

References 121 publications

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“…It has clear benefits for the treatment of sickle cell disease, as well as some types of cancer, myeloproliferative disorders, thalassemias, and HIV infection (25). The long-term effects of HU treatment were recently reported in a 17.5-y follow-up of adults undergoing HU therapy, with no difference in the incidence of stroke, organ dysfunction, infection, or cancer reported between treated individuals and controls (56).…”

Section: Discussionmentioning

confidence: 99%

“…As a result, HU-treated patients have fewer vasoocclusive events and require fewer transfusions and hospitalizations (24). HU treatment is therefore an effective drug for long-term management of sickle cell disease (21) and other disorders, including certain cancers, myeloproliferative disorders, thalassemias, and HIV infection (25). Here we examined the effects of therapeutic doses of HU on CNV formation in normal human fibroblasts.…”

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confidence: 99%

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Hydroxyurea induces de novo copy number variants in human cells

Arlt¹,

Ozdemir²,

Birkeland

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

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Copy number variants (CNVs) are widely distributed throughout the human genome, where they contribute to genetic variation and phenotypic diversity. Spontaneous CNVs are also a major cause of genetic and developmental disorders and arise frequently in cancer cells. As with all mutation classes, genetic and environmental factors almost certainly increase the risk for new and deleterious CNVs. However, despite the importance of CNVs, there is limited understanding of these precipitating risk factors and the mechanisms responsible for a large percentage of CNVs. Here we report that low doses of hydroxyurea, an inhibitor of ribonucleotide reductase and an important drug in the treatment of sickle cell disease and other diseases induces a high frequency of de novo CNVs in cultured human cells that resemble pathogenic and aphidicolin-induced CNVs in size and breakpoint structure. These CNVs are distributed throughout the genome, with some hotspots of de novo CNV formation. Sequencing revealed that CNV breakpoint junctions are characterized by short microhomologies, blunt ends, and short insertions. These data provide direct experimental support for models of replication-error origins of CNVs and suggest that any agent or condition that leads to replication stress has the potential to induce deleterious CNVs. In addition, they point to a need for further study of the genomic consequences of the therapeutic use of hydroxyurea.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hydroxyurea induces de novo copy number variants in human cells

Arlt¹,

Ozdemir²,

Birkeland

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

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“…Also, it inhibits the incorporation of thymidine into DNA, and may directly damage DNA (McEvoy 2006;BristolMyers Squibb Canada, 2006). Hydroxyurea is rapidly metabolized to nitroxide compounds including nitric oxide that are responsible for physiologic and toxic effects (Yarbro, 1992;Koviac, 2011). These nitroxides act as free radicals induce formation of reactive oxygen causing oxidative stress, interacting with nucleic acids and proteins to impair cellular functions (Koviac, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxyurea is rapidly metabolized to nitroxide compounds including nitric oxide that are responsible for physiologic and toxic effects (Yarbro, 1992;Koviac, 2011). These nitroxides act as free radicals induce formation of reactive oxygen causing oxidative stress, interacting with nucleic acids and proteins to impair cellular functions (Koviac, 2011). Regarding to the present hematological results, significant decrease in RBCs count, Hb concentration and HCT values with normocytic normochromic anemia were evident during the second period of the experiment, while at the first 10 days, there was significant decrease in these parameter in HU 750 group only.…”

Section: Discussionmentioning

confidence: 99%

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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“…The injury progresses until cellular repair mechanisms are no longer able to regenerate keratinocytes and endothelial cells [8,9].…”

Section: Discussionmentioning

confidence: 99%

Development of Genital Ulcer due to Hydroxyurea Treatment in a Patient with Polycythemia Vera - A Case Report

González¹

2017

Austin J Dermatolog

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Genital ulcers due to Hydroxyurea treatment, is a very rare entity that requires the skills of dermatology specialists to suspect and diagnose it in early stages. We present a case of 48 years old female with history of polycythemia vera under treatment of Hydroxyurea during 10 years. She developed a painful genital ulcer in 15 days without any other manifestations. Herpetic etiology, HIV and primary syphilis were rejected. The skin biopsy specimen revealed neoangiogenesis associated with lymphoplasmocytic perivascular inflammatory infiltrate without evidence of vasculitis. There was a completely resolution of the lesions, 8 weeks after Hydroxyurea cessation. The patient was referred to the oncology service to continue her hematologic treatment.

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Hydroxyurea (therapeutics and mechanism): Metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications

Cited by 47 publications

References 121 publications

Hydroxyurea induces de novo copy number variants in human cells

Hydroxyurea induces de novo copy number variants in human cells

Hematocytological Evaluation of Hydroxyurea-Induced Toxicity in Male Rats

Development of Genital Ulcer due to Hydroxyurea Treatment in a Patient with Polycythemia Vera - A Case Report

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