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PubMed1979

The effects of concanavalin A, cerulenin, hydroxyurea and tunicamycin on the incorporation of amino acids and glucosamine in Tetrahymena pyriformis.

1. Pulse labelling of conjugating Tetrahymena pyriformis with glycine and glucosamine gave results consistent with a requirement for de novo synthesis of a lipid-like component which is involved in the addition of sugar to cell glycoprotein. 2. Conjugation of complementary strains of Tetrahymena can be inhibited without gross morphologic and metabolic changes in the cells. The observed inhibition of conjugation is reversible. 3. Concanavalin A stopped conjugation and stimulated both glycine and glucosamine incorporation. 4. Tunicamycin inhibited conjugation but had little influence on total glucosamine incorporation. Amino acid incorporation was slightly enhanced. 5. Hydroxyurea blocked conjugation, inhibited the incorporation of glucosamine and seemed to induce a transient increase in glycine incorporation. 6. Cerulenin inhibited conjugation but had little effect on the incorporation of glycine and glucosamine into the cell.

Amino Acids↗

PubMed1978

3' deoxycytidine, like hydroxyurea, inhibits DNA synthesis without preventing the initiation of the cell cycle.

3' Deoxycytidine, the cytidine analogue of cordycepin and selective inhibitor of pre-ribosomal RNA in HeLa cells, has been found to be a reversible inhibitor of DNA replication in RNA accumulation. Like other inhibitors of DNA replication such as hydroxyurea, it does not prevent serum-stimulated quiescent 3T3 cells from undergoing the random transition which is rate-limiting for entry into S phase.

Cell Cycle↗

PubMed1992

A gene (hur) from Streptomyces aureofaciens, conferring resistance to hydroxyurea, is related to genes encoding streptomycin phosphotransferase.

A novel gene (hur) conferring resistance to hydroxyurea (HU) in Escherichia coli has been identified in a Streptomyces aureofaciens genomic library. The expression of hur in E. coli was under the control of the external plasmid tet promoter. Sequence analysis of a minimal fragment revealed an open reading frame (ORF) encoding a protein of 340 amino acids with an M(r) of 36,049 and an average hydropathy index of 1.13. The predicted protein product was similar to streptomycin phosphotransferases from Streptomyces glaucescens and Streptomyces griseus (52.4% and 50.8% identity, respectively), but it did not confer resistance to streptomycin or to any of the other aminoglycoside antibiotics tested. It is inferred that hur encodes a phosphotransferase that inactivates HU by phosphorylation of the hydroxy group in the hydroxylamine moiety.

Amino Acid Sequence↗

PubMed1995

Anticancer drug toxicity via cytokine production: the hydroxyurea paradigm.

Our previous observations on the toxic effects of hydroxyurea (HU) in adrenalectomized (ADX) rats prompted us to suggest that these effects might be mediated by an increased synthesis of proinflammatory cytokines. This study was conducted to determine whether HU stimulates cytokine gene expression in vivo. The polymerase chain reaction (PCR) technique was used to assess levels of mRNA for interleukin-1 alpha (IL-1 alpha), tumor necrosis factor (TNF) and interleukin-4 (IL-4) in spleen cells from intact and ADX rats treated with HU or vehicle. In ADX rats, expression of proinflammatory-cytokine mRNA was markedly increased by HU, but no expression of these genes was seen in intact animals after treatment. In the latter rats, cytokine-gene expression seemed to be down-regulated by HU-induced elevations in plasma corticosterone levels, since IL-1 alpha and TNF transcripts could be detected only after corticosterone levels had returned to normal (24 h after treatment). Interestingly, IL-4 mRNA could not be detected in either treated or untreated ADX rats, indicating that expression of this gene is closely related to circulating levels of corticosterone. These findings strongly suggest that the increased toxicity displayed by HU in ADX animals is mediated by stimulation of cytokine synthesis in vivo.

Adrenalectomy↗

PubMed1996

The effects of inhibitors of cyclo-oxygenase, lipoxygenase and nitric oxide synthase pathways on the toxicity of hydroxyurea in adrenalectomized rats.

Our previous observations on the toxic effects of hydroxyurea (HU) in adrenalectomized (ADX) rats prompted us to suggest that these effects might be mediated by an increased synthesis of proinflammatory cytokines, which display similar toxicological profiles (e.g. increased lethality in adrenal-ablated animals). The present study was aimed at investigating whether some of the mediators of the biological effects of pro-inflammatory cytokines (i.e. prostaglandins, leukotrienes, and nitric oxide) are involved in the severe HU toxicity seen in ADX rats. The latter were treated over a 5-day period with HU alone or HU plus specific inhibitors of prostaglandin, leukotriene and nitric oxide synthetic pathways. Mortality was recorded throughout the experiments. Results showed that, while corticosterone and dexamethasone afford significant protection against HU toxicity, the latter is not reduced and may even be aggravated by treatments with specific inhibitors of cyclo-oxygenase, lipoxygenase or nitric oxide synthase.

Adrenalectomy↗

PubMed1992

Determination by high-performance liquid chromatography of hydroxyurea in human plasma.

An assay using reversed-phase high-performance liquid chromatography with electrochemical detection was developed to measure hydroxyurea in plasma at concentrations suitable for pharmacokinetic studies. The sample preparation is simple, the analysis rapid and assays can be batched. The between-run precision is excellent (coefficient of variation = 2.8-4.5%) and the limit of detection is 0.02 mmol/l. Preliminary studies have shown that the method is suitable for pharmacokinetic studies.

Chromatography, High Pressure Liquid↗

PubMed1990

The nature of the embryo-protective interaction of propyl gallate with hydroxyurea.

Hydroxyurea (HU) is a swiftly acting cytotoxic teratogen and an inhibitor of DNA synthesis. Within 2 h of maternal treatment, HU causes necrosis in proliferating tissues of rabbit embryos on gestational day 12. Co-administration of the antioxidant propyl gallate (PG) delays the onset of necrosis until 6 h and ameliorates the teratogenic effects seen at term. Since HU also causes a rapid, profound decrease in uterine blood flow in pregnant rabbits, it is necessary to determine whether HU and PG interact within the pregnant female or within the embryo. In order to establish that the site of HU-PG interaction is embryonic, HU, PG, HU-PG, or vehicle was injected directly into implantation sites. When embryos were examined microscopically at 4 h, necrosis was observed only in the HU-treated embryos, indicating that the palliative interaction between HU and PG takes place within the embryo. To resolve whether the alleviation of HU-induced embryotoxicity was due to decreased HU levels within HU-PG embryos, HU concentrations were measured in embryos from HU-and HU-PG-treated maternal rabbits at 15 min to 8 h post injection. The HU levels of the two groups differed significantly only at 4 h. The rates of uptake during the linear phase (times from 15 min to 3 h) did not differ. When HU concentration was plotted versus time, measurements of the areas under the curve also did not differ. To determine whether PG alters the HU-induced inhibition of DNA synthesis, 3H-thymidine incorporation into embryonic DNA was assayed at 2 h after HU, HU-PG, or vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMed1990

Ethoxyquin and nordihydroguaiaretic acid reduce hydroxyurea developmental toxicity.

Hydroxyurea (HU) is a potent teratogen that causes a characteristic, rapidly occurring episode of embryonic cell death 2 to 4 h after subcutaneously injecting 650 mg/kg of HU into pregnant New Zealand White rabbits on gestational day 12. Previous studies documented the ability of the phenolic antioxidant, propyl gallate, to delay the onset of embryonic cell death and to decrease the number and severity of defects seen at term. The present study investigated the ability of the structurally different antioxidants, ethoxyquin (ETX) and nordihydroguaiaretic acid (NDGA), to also ameliorate HU developmental toxicity. Injection of pregnant rabbits with either ETX or NDGA at 950 mg/kg, 15 to 30 min prior to HU injection, resulted in reduced developmental toxicity seen at term. The reduction was manifested by fewer malformed fetuses with increased body weights compared with fetuses from HU-only treated litters, greatly reduced incidences of specific malformations, and diminished severity of some HU-induced defects. Microscopic analysis of HU, HU-ETX, and HU-NDGA embryos was performed at 4 or 8 h after treatment. HU caused cell death in the limb bud mesenchyme, clearly evident at 4 h. In contrast, HU-NDGA embryos exhibited no signs of cell death until 8 h after treatment. Although most HU-ETX embryos exhibited little or no cell death at 4 h after treatment, in about 20% the level of cell death was indistinguishable from that in HU-treated embryos. The amelioration of HU developmental toxicity in the present study is consistent with the results of previous studies utilizing propyl gallate. The results suggest that the antioxidant properties of these substances interfere with the rapidly occurring toxic effects of HU and that this may account for amelioration of HU developmental toxicity.

Abnormalities, Drug-Induced↗

PubMed1989

ESR studies of structure and kinetics of radicals from hydroxyurea. An antitumor drug directed against ribonucleotide reductase.

Hydroxyurea (HU) is a clinically applied antineoplastic drug, which quenches tyrosine radicals in the active site of ribonucleotide reductase (RR) and inhibits DNA synthesis in proliferating cells. Under oxidizing conditions (Cu2+ or H2O2) long-lived radicals from HU have been found by ESR. The structure of HU radicals was established to be: (formula; see text). The kinetics of formation and decay of HU radicals after reaction of HU with H2O2 is complex; it exhibits a lag-phase, a maximum, and a decay, all depending on the concentration of HU. Biological consequences of HU radicals for the inhibition of RR as well as their role in cytotoxic events during chemotherapy of cancer are discussed.

Antineoplastic Agents↗

PubMed2004

In vivo examination of hydroxyurea and the novel ribonucleotide reductase inhibitors trimidox and didox in combination with the reverse transcriptase inhibitor abacavir: suppression of retrovirus-induced immunodeficiency disease.

Inhibition of ribonucleotide reductase (RR) has gained attention as a potential strategy for HIV-1 therapy through the success of hydroxyurea (HU) to potentiate the activity of the nucleoside reverse transcriptase inhibitor (NRTI) didanosine (ddI) in clinical trials. However, the use of HU has been limited by its development of hematopoietic toxicity. In this study, the novel RR inhibitors didox (DX; 3,4-dihydroxybenzohydroxamic acid), and trimidox (TX; 3,4,5-trihydroxybenzamidoxime) were evaluated along with HU for anti-retroviral efficacy in LPBM5-induced retro-viral disease (MAIDS) both as monotherapeutic regimens and in combination with the guanine containing NRTI abacavir (ABC). Anti-retroviral drug efficacy was determined by measuring inhibition of splenomegaly, hypergammaglobulinemia, and splenic levels of proviral DNA. In this study, all RRIs tested showed the ability to improve the efficacy of ABC in the MAIDS model by reducing splenomegaly, hypergammaglobulinemia, and splenic proviral DNA levels.

Animals↗

PubMed2005

Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease.

The ribonucleotide reductase inhibitor hydroxyurea (HU) has demonstrated some benefit as a component of drug cocktails for the treatment of HIV-1 infection. However, HU is notoriously myelosuppressive and often administered only as salvage therapy to patients with late-stage disease, potentially exacerbating the bone marrow toxicity of HU. In this report we have compared the antiviral effects of HU and two novel RR inhibitors trimidox (3,4,5-trihydroxybenzamidoxime) and didox (3,4-dihydroxybenzohydroxamic acid) in combination with didanosine (2,3-didoxyinosine; ddI) in the LPBM5 MuLV retrovirus model (murine AIDS). We also evaluated the effects of these drug combinations on the hematopoietic tissues of LPBM5 MuLV-infected animals. The combination of RR inhibitors and ddI was extremely effective (DX>TX>HU) in inhibiting development of retrovirus-induced disease (splenomegaly, hypergammaglobulinemia, activated B-splenocytes and loss of splenic architecture). In addition, relative levels of proviral DNA were significantly lower in combination drug-treated animals compared to infected controls. Evaluation of femur cellularity, numbers of marrow-derived myeloid progenitor cells (CFU-GM and BFU-E) and peripheral blood indices revealed that TX and DX in combination with ddI were well-tolerated. However, treatment with HU and ddI induced moderate myelosuppression. These data demonstrate that RR inhibitors in combination with ddI provide significant protection against retroviral disease in murine AIDS. Moreover, the novel RR inhibitors TX and DX appear to be more effective and less myelosuppressive than HU when administered with ddI in this model.

Animals↗

PubMed2004

Nitroxyl (HNO) release from new functionalized N-hydroxyurea-derived acyl nitroso-9,10-dimethylanthracene cycloadducts.

A thermal retro-Diels-Alder decomposition of N-hydroxyurea-derived acyl nitroso compounds and 9,10-dimethylanthracene cycloadducts followed by acyl nitroso compound hydrolysis produces nitrous oxide, evidence for the formation of nitroxyl, the one-electron reduced form of nitric oxide that has drawn considerable attention for its potential roles in biological systems. EPR and NMR spectroscopy provide further evidence for nitroxyl formation and kinetic information, respectively. Such compounds may prove to be useful alternative nitroxyl donors.

Anthracenes↗

PubMed2006

Exploring alternative Zn-binding groups in the design of HDAC inhibitors: squaric acid, N-hydroxyurea, and oxazoline analogues of SAHA.

Analogues of suberoylanilide hydroxamic acid (SAHA) were prepared by replacing the Zn-binding group with squaric acid, N-hydroxyurea, and 4-hydroxymethyl oxazoline units, also varying the length of the aliphatic chain. No inhibitory activity on HDAC was observed below 1.0 microM and no cytotoxic activity on different tumor cell lines was seen below 20.0 microM.

Alkynes↗

PubMed2006

Synthesis, aerobic cytotoxicity, and radiosensitizing activity of novel 2,4-dinitrophenylamine tethered 5-fluorouracil and hydroxyurea.

Two novel dual functional agents, 3[3-(2,4-dinitro-phenylamino)-propyl]-5-fluoro-1H-pyrimidine-2,4-dione 7 and N-[3-(2,4-dinitro-phenylamino)-propoxy]urea 8, resulting from linkage of 2,4-dinitrophenylamine through three carbon atoms with 5-fluorouracil 5 and hydroxyurea 6, respectively, were prepared and their in vitro aerobic cytotoxicities in HT-29 cell line with and without radiation were determined. Compounds 7 and 8 unlike their components were not cytotoxic but showed radiosensitizing activity.

Aerobiosis↗

PubMed2005

Effects of hydroxyurea treatment on cerebral oxygenation in adult patients with sickle cell disease: an open-label pilot study.

BACKGROUND: In patients with sickle cell disease (SCD), cerebral oxygen saturation (rSO(2)) has been reported to be below normal and to increase after red blood cell transfusion. OBJECTIVE: This study was designed to determine the effects of long-term and short-term hydroxyurea (HU) treatment on cerebral oxygenation in patients with SCD. METHODS: This open-label pilot study was conducted at the Department of Anesthesiology and the Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC. Adult African American outpatients with SCD and hemoglobin (Hb) genotype HbSS (homozygous sickle Hb) who were receiving long-term (>6 months) HU treatment (15-30 mg/kg . d PO) or who had never received this treatment (control group) were enrolled. Patients in the treated and control groups were matched for age, sex, race, and Hb genotype. Cerebral oximetry (near-infrared spectroscopy) was performed to determine rSO(2) index. In a separate analysis to determine the effects of short-term HU treatment on cerebral oxygenation, hospitalized patients with SCD and vaso-occlusive crisis (VOC)receiving long-term therapy with HU were enrolled. We performed cerebral and pulse (fingernail) oximetry to determine rSO (2)index and arterial oxygen saturation (SpO(2)) after the administration of a single oral dose of HU (500-mg tablet) alone and again after dosing concomitantly with inhaled oxygen. RESULTS: The study enrolled 11 patients in the HU group (6 women, 5 men; mean [SD] age, 37 [8] years) and 20 controls (8 women, 12 men; mean [SD] age, 35 [6] years). Mean (SD) rSO(2) index was significantly increased (but still low) in patients receiving long-term HU treatment compared with controls (46.1% [6.6%] vs 41.2% [7.6%]; P< 0.025). Hb concentration (9.6 [1.4] g/dL vs 8.5 [1.2] g/dL; P< 0.027), hematocrit (28% [3%] vs 24% [4%]; P < 0.028), and mean corpuscular volume (102% [7%] vs 89% [8%]; P < 0.027) also were significantly higher in the HU group compared with controls. In 8 patients with SCD and VOC (6 men, 2 women; mean [SD] age, 28 [5] years), single-dose HU, either alone or in combination with inhaled oxygen, did not significantly affect cerebral oxygenation, and SpO(2) failed to correlate with rSO(2) index in these patients. CONCLUSIONS: The results of this open-label pilot study in patients with SCD suggest that the low cerebral oxygenation in these patients is significantly improved but not normalized with long-term HU treatment. A single dose of HU, either alone or in combination with inhaled oxygen, did not appear to influence cerebral oxygenation in patients with VOC.

Adult↗

PubMed2004

Effects of prenatal hydroxyurea-treatment on mouse offspring.

Hydroxyurea (HU), a ribonucleotide reductase inhibitor, induces morphological anomalies in the central nervous system, craniofacial tissues and limb buds in animals, and neonatal respiratory distress in humans. The neonates and offspring of pregnant mice treated with 400 or 800 mg/kg of HU on day 13 of gestation were examined at 0 day and 10 weeks after birth to find a clue for clarifying the relationship between HU-induced apoptosis in the fetal tissues and teratogenicity. The offspring from dams treated with HU were retarded in growth compared with controls. But there was no significant difference in the body weight gain between the 400 and 800mg/kg groups. In the teratologic changes, microencephaly, hydrocephalus and curved coccygeal vertebrae were observed in the offspring, and the incidence of these teratologic changes was similar but their degree was more severe in the 800 mg/kg group than in the 400 mg/kg group. Based on the above-mentioned previous and present studies of ours, we suggest that HU-induced apoptosis in fetal tissues may play an important role in the development of anomalies in the corresponding tissues of offspring.

Abnormalities, Drug-Induced↗

PubMed2005

Insights into elevated distortion product otoacoustic emissions in sickle cell disease: comparisons of hydroxyurea-treated and non-treated young children.

Distortion product otoacoustic emissions (DPOAEs) were examined in 15 normal-hearing African-American children between the ages of 6 and 14 years with homozygous sickle cell disease (SCD), who were on a regimen of hydroxyurea (HDU), a drug that reduces inflammatory processes and symptoms of SCD; a matched group of 15 African-American children with homozygous SCD not on HDU; and 15 African-American children with normal hemoglobin. DPOAEs were evoked by 13 primary tone pairs with f2 frequencies ranging from 1000 to 4500 Hz. Increased DPOAE amplitudes, believed to be a precursor of eventual hearing loss, were evident in children with SCD who were not receiving HDU. Those taking HDU had DPOAE amplitudes similar to normal controls. These findings suggest that HDU, in addition to reducing symptoms of SCD, may play a role in inhibiting or preventing cochlear pathology and hearing loss in individuals with SCD.

Adolescent↗

PubMed2006

Oxidation of hydroxyurea with oxovanadium(V) ions in acidic aqueous solution.

Hydroxyurea (HU) effectively reduces vanadium(V) into vanadium(IV) species (hereafter V(V) and V(IV) species, respectively) in acidic aqueous solution via the formation of a transient complex followed by an electron transfer process that includes the formation and subsequent fading out of a free radical, U* (U* identical with H(2)N-C(=O)N(H)O*). The electron paramagnetic resonance (EPR) spectra of U* in H(2)O/D(2)O solutions suggest that the unpaired electron is located predominantly on the hydroxamate hydroxyl-oxygen atom. Visible and V(IV)-EPR spectroscopic data reveal HU as a two-electron donor, whereas formation of U*, which reduces a second V(V), indicates that electron transfer occurs in two successive one-electron steps. At the molarity ratio [V(V)]/[HU]=2, the studied reaction can be formulated as: 2 V(V)+HU-->2 V(IV)+0.98 CO(2)+0.44 N(2)O+1.1 NH(3)+0.1 NH(2)OH. Lack of evidence for the formation of NO is suggested to be a consequence of the slow oxidation of HNO due to the too low reduction potential of the V(V)/V(IV) couple under the experimental conditions used. The nuclear magnetic resonance ((51)V-NMR) spectral data indicate protonation of (H(2)O)(4)V(V)O(2)(+), and the protonation equilibrium constant was determined to be K=0.7 M(-1). Spectrophotometric titration data for the V(V)-HU system reveal formation of (H(2)O)(2)V(V)O(OH)U(+) and (H(2)O)(3)V(V)OU(2+). Their stability constants were calculated as K(110)=5 M(-1) and K(111)=22 M(-2), where the subscript digits refer to (H(2)O)(4)V(V)O(2)(+), HU and H(+), respectively.

Electron Spin Resonance Spectroscopy↗