Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea is well absorbed after oral administration, converted to a free radical nitroxide in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replitase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen. Synergy has also been observed between hydroxyurea and a number of other chemotherapeutic agents, including cytarabine and etoposide. Recently, two new effects of hydroxyurea have been observed: hydroxyurea increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia, and hydroxyurea selectively reduces the level of episomal DNA and thus potentially may reduce drug resistance associated with duplicated genes retained as episomes. Further exploration of the efficacy of hydroxyurea in combination with other therapeutic agents is warranted.
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PMID:Mechanism of action of hydroxyurea. 164 48

The metabolism of nitrovasodilators such as glyceryl trinitrate and nitroprusside provides the active moiety of these drugs (that is, nitric oxide). This process is not limited to the known nitrovasodilators, but also occurs with nitroaromatic antimicrobials. Here we report that the administration of hydroxyurea, an antitumor drug, to rats at pharmacological doses formed detectable nitrosyl hemoglobin, which increased with dose. At higher doses, nitrosyl hemoprotein complexes could also be detected in liver tissue. [15N]hydroxyurea was synthesized and compared with [14N]hydroxyurea. These observations verified that nitric oxide detected as nitrosyl hemoglobin or nitrosyl hemoprotein complexes in rats was the result of the metabolism of hydroxyurea. The time course and dose-dependence of nitric oxide generation were also investigated. Hydroxyurea's antineoplastic activity is caused by its direct action on ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. Because nitric oxide also inhibits ribonucleotide reductase, this metabolite may supplement this action of hydroxyurea. In addition, the known ability of hydroxyurea to ease the pain of sickle cell anemia patients may be the result of vasodilation by the drug-derived nitric oxide.
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PMID:In vivo production of nitric oxide in rats after administration of hydroxyurea. 941 18

Trimidox (3,4,5-trihdroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase with accompanied growth inhibition and differentiation of mammalian cells. Hydroxyurea (HU) is the only ribonucleotide reductase inhibitor in clinical use for the treatment and management of sickle cell anemia, since this compound increases fetal hemoglobin (Hb F) production: a potent inhibitor of sickle hemoglobin (Hb SS) polymerization. However, the main limitations of HU is its lack of potency, myelosuppression and short half life. These studies investigated the effects of trimidox on the induction of hemoglobin and F-cells production in K562 erythroleukemia cells. Our study reveals that trimidox exhibits concentration dependent inhibitory effect on K562 cells with increase in benzidine positive normoblasts and F-cells production as well as morphological changes typical of erythroid differentiation. These findings provide the first evidence that the growth inhibitory differentiation of cells induced by trimidox enhance hemoglobin and F-cells production.
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PMID:Trimidox-mediated morphological changes during erythroid differentiation is associated with the stimulation of hemoglobin and F-cell production in human K562 cells. 964 67

Hydroxyurea is a common cancer chemotherapy agent that inhibits ribonucleotide reductase, an enzyme essential to DNA synthesis. It is considered the drug of choice in the treatment of chronic myelogenous leukemia and essential thrombocythemia. The occurrence of leg ulcers have been described in 8.5% of patients receiving continuous treatment with hydroxyurea, but the cause of this complication is unknown. We report two additional patients and suggest that macroerythrocytosis, which occurs in almost all the patients taking hydroxyurea, may be a pathogenic factor. Macroerythrocytosis can be considered as an 'acquired' blood dyscrasia, and similar leg ulcers have long been known to occur with certain hereditary blood dyscrasias, such as sickle cell anemia, thalasemia, and spherocytosis.
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PMID:Hydroxyurea-induced leg ulcers: is macroerythrocytosis a pathogenic factor? 1046 46

Upon appropriate drug treatment, the human erythroleukemic K562 cells have been shown to produce hemoglobin and F-cells. Fetal hemoglobin (Hb F) inhibits the polymerization events of sickle hemoglobin (Hb S), thereby ameliorating the clinical symptoms of sickle cell disease. Ribonucleotide reductase inhibitors (RRIs) have been shown to inhibit the growth of myeloid leukemia cells leading to the production of Hb F upon differentiation. Of the RRIs currently in use, hydroxyurea is the most effective agent for Hb F induction. We have examined the capacity of two novel RRIs, didox (DI) and trimidox (TRI), in combination with streptozotocin (STZ), to induce hemoglobin and F-cell production. The K562 cells were cultured with different concentrations of didox-STZ or trimidox-STZ at a fixed molar ratio of 3:1 and 1:5 for 96 hr, respectively. At pre-determined time intervals, aliquots of cells were obtained and total hemoglobin (benzidine positive) levels, number of F-cells, and Hb F were determined by the differential staining technique, fetal hemoglobin assay kit, and fluorescence cytometry respectively. The effect of combined drug treatment on the growth of K562 cells was examined by isobologram analysis. Our results indicate that a synergistic growth-inhibitory differentiation effect occurred when didox or trimidox was used in combination with STZ on K562 cells. There was an increase in the number of both benzidine-positive normoblasts and F-cells, accompanied by morphologic appearances typical of erythroid maturation. On day 4, the number of benzidine-positive cells showed a 6-9-fold increase and the number of F-cells was between 2.5- and 5.7-fold higher than the respective controls. Based upon these results, treatment with a ribonucleotide reductase inhibitor, such as didox or trimidox, in combination with STZ, might offer an additional promising option in sickle cell disease therapy.
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PMID:Enhancement of hemoglobin and F-cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (didox and trimidox) in combination with streptozotocin. 1070 60

Hydroxyurea has been extensively used in medical practice, mainly for treating chronic myelogenous leukemia, sickle cell anemia, and other diseases. In light of its ability to inhibit DNA synthesis and to induce cell cycle arrest through inhibition of ribonucleotide reductase, the effects of hydroxyurea on replication of human immunodeficiency virus type 1 (HIV-1) have been investigated. In vitro hydroxyurea has been shown to block HIV-1 reverse transcription and/or replication in quiescent peripheral blood mononuclear cells (PBMC) and macrophages. Hydroxyurea was also found to be synergistic with the nucleoside reverse transcriptase inhibitor didanosine and to inhibit HIV-1 replication in activated PBMC; this inhibition may be due to a reduction in deoxynucleoside triphosphate pool sizes. Finally, hydroxyurea has been shown to sensitize didanosine-resistant mutants. Hydroxyurea may therefore be useful for limiting the spread of didanosine-resistant HIV-1 variants. The favorable toxicity profile of hydroxyurea and the lack of significant overlapping toxicities with some of the nucleoside reverse transcriptase inhibitors, as well as their distinct mechanisms of action, have provided further rationale for use of these agents in combination therapies.
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PMID:Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug. 1086 Sep 5

Lithium has been known for its ability to induce the production of hematopoietic cells following administration in vivo to minimize the toxic effects on hematopoiesis as a consequence of drug treatment. The drug hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been used in the treatment of a variety of neoplastic and non-neoplastic diseases, such as cancer and sickle cell anaemia. Hydroxyurea has more recently been implicated for use in the treatment of acquired immunodeficiency syndrome (AIDS). However, its major limitations have been due to its toxicity. Hydroxyurea selectively inhibits DNA synthesis and due to its brief duration, the drug is only toxic to those cells which are selectively synthesizing DNA during the period of exposure. The most important of these toxicities, and which serves as a dose limiting factor in treatment, is the induction of bone marrow suppression. In this study we investigated the possible beneficial effects of administering lithium (LiCl) to murine leukemia virus (MuLV) infected and non-infected long term bone marrow cultures (LTBMC). These cultures were then treated with either 0.2 mM hydroxyurea, 1.0 mM LiCl, or a combination of both. Samples were collected from LTBMC supernatants at 1, 2, 3, 4, 5 and 6 weeks post-treatment. Culture supernatants were then monitored to observe their repopulation of hematopoietic progenitors. The results demonstrated the effects of lithium in restoring hydroxyurea suppressed numbers of myeloid (CFU-GM) progenitors to within a normal range and also in re-establishing erythroid (BFU-E) progenitors.
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PMID:The effects of lithium in reversing hydroxyurea induced suppression of hematopoietic progenitor cells in vitro using retroviral infected long-term marrow cultures. 1100 Aug 67

Hydroxyurea (HU) is an anti-neoplastic agent that may have potential to be used as part of a combination HIV drug regimen. Hydroxyurea seems to make standard antiretroviral drugs more potent and longer acting. It has been used in the past to treat a variety of malignancies and sickle cell anemia, is relatively safe, well tolerated, and inexpensive. The first reports of hydroxyurea's ability to inhibit HIV replication were published in 1994. The drug works by inhibiting ribonucleotide reductase, essential in HIV's ability to produce DNA. Early test results are presented. HU's easy availability and good safety profile make it an attractive addition to HIV combination therapy.
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PMID:Hydroxyurea may enhance effectiveness of anti-HIV regimens presently in use. 1136 24

Resveratrol, a natural dietary polyphenol, has been postulated to be implicated in the cardioprotective effect of red wine and the low incidence of breast and prostate cancers among vegetarians and Orientals respectively. This compound inhibits ribonucleotide reductase as does hydroxyurea, the first therapeutic agent used in the treatment of sickle cell disease. Using the human erythroleukaemic K562 cell line as an in vitro model, we show here that 50 micromol/l of resveratrol induced a higher haemoglobin production (sevenfold) in K562 cells than 500 micromol/l of hydroxyurea (3.5-fold). This erythroid differentiation was linked to a dose- and time-dependent inhibition of cell proliferation associated with an equivalent increased expression of p21 mRNA, but with a higher increased level of p21 protein (sixfold) for cells treated with resveratrol than for those treated with hydroxyurea (1.5-fold). We also show that 50 micromol/l of resveratrol and 25 micromol/l of hydroxyurea induced variable but similar enhancements of fetal haemoglobin synthesis in cultured erythroid progenitors for the majority of the sickle cell patients studied. These inductions were linked to, but not correlated with, a variable decrease in erythroid burst-forming unit clone number. Taken together, these results show that resveratrol merits further investigations in sickle cell disease therapy.
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PMID:Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea towards erythroid differentiation. 1138 Apr 23

Hydroxyurea is used to treat a variety of cancers and sickle cell disease. Despite this widespread use, a complete mechanistic understanding of the beneficial actions of this compound remains to be understood. Hydroxyurea inhibits ribonucleotide reductase and increases the levels of fetal hemoglobin, which explains a portion of the effects of this drug. Administration of hydroxyurea to patients results in a significant increase in levels of iron nitrosyl hemoglobin, nitrite and nitrate suggesting the in vivo metabolism of hydroxyurea to nitric oxide. Formation of nitric oxide from hydroxyurea may explain a portion of the observed effects of hydroxyurea treatment. At the present, the mechanism or mechanisms of nitric oxide release, the identity of the in vivo oxidant and the site of metabolism remain to be identified. Chemical oxidation of hydroxyurea produces nitric oxide and nitroxyl, the one-electron reduced form of nitric oxide. These oxidative pathways generally proceed through the nitroxide radical (2) or C-nitrosoformamide (3). Biological oxidants, including both iron and copper containing enzymes and proteins, also convert hydroxyurea to nitric oxide or its decomposition products in vitro and these reactions also occur through these intermediates. A number of other reactions of hydroxyurea including the reaction with ribonucleotide reductase and irradiation demonstrate the potential to release nitric oxide and should be further investigated. Gaining an understanding of the metabolism of hydroxyurea to nitric oxide will provide valuable information towards the treatment of these disorders and may lead to the development of better therapeutic agents.
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PMID:The nitric oxide producing reactions of hydroxyurea. 1257 Jun 92


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