SEARCH · PubMed Health

Results for “hydroxyurea”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,063 records · Page 59Linked to original sources

PubMed1994

Hydroxyurea enhances 3'-azido-3'-deoxythymidine (AZT) cytotoxicity in human chronic myeloid leukemia models.

In this report we have evaluated the cytotoxic activity of 3'-azido-3'-deoxythymidine (AZT) used in combination with hydroxyurea (HU), an agent which disrupts de novo thymidylate synthesis. In 2 chronic myeloid leukemia (CML) cell lines, K562 and RWLeu4, the IC50 of AZT was 8 mumol/l and 28 mumol/l respectively, after a 5-day exposure, and the IC50 of HU was 80 mumol/l and 70 mumol/l respectively. In the presence of various concentrations of HU (1 mumol/l-100 mumol/l) the IC50 of AZT in both cell lines was significantly reduced and subsequent isobologram analysis revealed synergistic activity. Similarly, analysis of [3H]AZT incorporation into the DNA fraction of these cells indicated that exposure to AZT+HU resulted in an increased incorporation of AZT into DNA when compared to incubation in AZT alone. Biochemically, this effect appeared to be related to a decrease in dTTP pools caused by HU. The combination AZT+HU has also been demonstrated to exert a synergistic effect in inhibiting colony growth of bone marrow granulocyte-macrophage progenitors (CFU-GM) from patients affected by Ph1+ CML in chronic phase. These results are promising in view of a possible in vivo utilization of this drug combination.

Bone Marrow↗

PubMed1994

Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications.

Fifty consecutive patients, 30 of whom had polycythaemia vera (PV), 10 essential thrombocythaemia (ET), and 10 myelofibrosis (MF), entered a long-term prospective study of hydroxyurea (HU) therapy. The indication for treatment was mainly thrombocytosis or symptomatic splenomegaly. Control of erythrocytosis and thrombocytosis was achieved in 70% of the patients. Continuous maintenance treatment was required. In 15% of responding patients with thrombocytosis, unexpected rises of the platelet count occurred during maintenance therapy. Severe thrombo-embolic events occurred in 6 patients. The size of the spleen decreased in all patients who did not develop thrombocytopenia and could absorb adequate HU doses. Acute leukaemia (AL) was diagnosed in 9 patients and a myelodysplastic syndrome in one. Seven of them had been treated with HU alone. Among the patients with PV and ET, 6 developed AL and 4 of them were treated with HU alone (3 PV and 1 ET), giving an incidence of 10.5%. In previously untreated patients with initially normal karyotypes (n = 19), chromosome abnormalities developed during HU therapy in 7 (37%). Our results indicate that HU should be regarded as leukaemogenic, at least when used for treatment of PV and allied diseases. Since myelosuppressive treatment of PV does not prolong survival, the use of HU should be restricted to patients in whom the treatment indication outweights the risk of leukaemia induction.

Acute Disease↗

PubMed1996

Monoclonal antibody-based methods for quantitation of hemoglobins: application to evaluating patients with sickle cell anemia treated with hydroxyurea.

High-titer monoclonal antibodies (mAb) were raised against chromatographically purified human hemoglobin (Hb) species. These mAb were specific for either Hb A, Hb F, Hb S or Hb C. Based on these antibodies, which were directly conjugated with either fluorochromes or an enzyme (horseradish peroxidase), we developed immunoassays for determining the Hb profile in the peripheral blood; an enzyme-linked immunosorbent assay (ELISA) for determining the absolute and relative quantities of various Hb species and one-step immunolabeling for fluorescence microscopic and flow cytometric analyses of the distribution of RBC with respect to their Hb types. We utilized these methods for monitoring the Hb F level and the percentage of Hb F-containing cells in patients with sickle cell anemia undergoing treatment with hydroxyurea.

Anemia, Sickle Cell↗

PubMed2004

Fulminant bronchiolitis obliterans organizing pneumonia following 2 d of treatment with hydroxyurea, interferon-alpha and oral cytarabine ocfosfate for chronic myelogenous leukemia.

A 65-yr-old man developed increasing dyspnea and fulminant respiratory failure 48 h after introduction of hydroxyurea, oral cytarabine ocfosfate (YNK01) and interferon-alpha for treatment of Philadelphia chromosome-positive chronic myelogenous leukemia. The chest radiograph showed bilateral patchy infiltrates while computed tomography revealed multiple bullas, ground glass opacities, and patchy consolidations with possible cavitation. Bronchoscopic examination was normal and microbiological tests performed on all biologic fluids were negative. The patient did not respond to multiple antibiotic treatment and corticosteroid administration and died of progressive respiratory failure 5 d after chemotherapy introduction. The postmortem lung examination was consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP).

Aged↗

PubMed1990

Hydroxyurea: relationship between toxicity and centrally-induced adrenal activation.

The anticancer drug hydroxyurea (HU) at doses of 300-800 mg/kg/day causes a dramatic lethality (up to 100% after a 5-day treatment) in hypophysectomized as well as in adrenalectomized rats drinking physiological saline + 5% glucose. Mortality in controls was less than 10% over a 5-day period. Adrenal stimulatory or replacement therapies protect pituitary- or adrenal-ablated rats against HU toxicity. They also counteract white blood cell changes induced by the drug. HU (30-800 mg/kg) induces a dose-dependent increase of plasma corticosterone in normal rats after single or repeated treatments that is not observed in hypophysectomized animals. HU also increases plasma levels of epinephrine, although this finding cannot account for the rise in plasma corticosterone; indeed, it is secondary to a strong rise in plasma corticosterone. The stimulation of the hypothalamic-hypophyseal-adrenal axis induced by HU is responsible for the drug-induced adrenocortical activation. This activation appears to be a valuable defence mechanism protecting intact rats against HU lethality, and its failure causes the dramatic HU lethality in pituitary- or adrenal-ablated animals.

Adrenal Glands↗

PubMed1998

Hemoglobin switching protocols in thalassemia. Experience with sodium phenylbutyrate and hydroxyurea.

Homozygous beta thalassemia affects thousands of people around the world. Current management of this condition includes regular transfusion of red cells, which leads to transfusional iron overload requiring chelation therapy: increasing hemoglobin levels while decreasing or eliminating iron overload is therefore a major therapeutic goal in the treatment of thalassemia. Bone marrow transplantation may achieve this goal, but it is not an option for most patients. This study reports on efforts to increase gamma-globin transcription and HbF production using sodium phenylbutyrate (SPB) and hydroxyurea (HU). It was found that 36% (4/11) of all patients or 50% (4/8) of non-transfused patients responded to SPB (increase in Hb levels of 1 g/dL). A positive correlation between baseline serum erythropoietin level and likelihood of response to SPB was observed. Since HU may also increase HbF production, evaluation of combination therapy with these drugs is underway and preliminary results are reported.

Antisickling Agents↗

PubMed2006

Depletion of glutathione induces 4-hydroxynonenal protein adducts and hydroxyurea teratogenicity in the organogenesis stage mouse embryo.

Glutathione (GSH) homeostasis is important during organogenesis. To elucidate the impact of GSH depletion in organogenesis stage embryos on oxidative stress and drug teratogenicity, l-buthionine-S,R-sulfoximine (BSO) was given to timed pregnant CD-1 mice 4 h before exposure to a model teratogen, hydroxyurea (HU) [400 mg/kg (HU-400) or 600 mg/kg (HU-600)]. Treatment with BSO or HU alone or with BSO plus HU-400 did not alter the ratios of glutathione disulfide/GSH in the embryo; in contrast, the combination of BSO plus HU-600 did increase this ratio at both 0.5 and 3 h post-HU, indicating the induction of oxidative stress in the embryos. Immunoreactivity to a product of lipid peroxidation, 4-hydroxynonenal (4-HNE) protein adducts, was detected in saline-treated embryos; the intensity and nuclear localization of 4-HNE protein adduct immunoreactivity in specific regions in the embryo was significantly increased by exposure to BSO alone or BSO and either dose of HU. BSO pretreatment increased the spectrum and incidence of external and skeletal malformations (curly tail, hind limb malformations, hydrocephaly, exencephaly, open eye, spina bifida, and gastroschisis) induced by HU-400 and HU-600; BSO exposure did not alter the effects of HU on fetal mortality or fetal weights or HU induction of c-Fos heterodimer-dependent activator protein 1 DNA binding activity. The formation of 4-HNE protein adducts in teratogen-exposed embryos was localized to regions of the embryo that were highly susceptible to insult, namely the somites and caudal neural tube, correlating the presence of 4-HNE adducts with the disruption of pattern formation during organogenesis.

Abnormalities, Drug-Induced↗

PubMed1963

HYDROXYUREA: MECHANISM OF ACTION.

Acetohydroxamic acid has been identified, by paper chromatography, in the blood of three patients with chronic myelogenous leukemia on hydroxyurea therapy. This suggests that the drug is hydrolyzed yielding hyroxylamine, which then cleaves thioesters, in particular acetyl-coenzyme A.

Blood Chemical Analysis↗

PubMed1972

An effect of hydroxyurea on Staphylococcus epidermidis: temporary loss of viability.

Although hydroxyurea (HU) is recognized as a specific inhibitor of deoxyribonucleic acid (DNA) synthesis, it did not have this effect in a strain of Staphylococcus epidermidis. In this case, HU caused a loss of colony-forming ability but did not prevent cell division in liquid medium. DNA synthesis apparently was affected only secondarily. About 10% of the population recovered colony-forming ability during the latter part of the growth cycle or when growth was slowed by chloramphenicol. Recovery also occurred when HU was removed from the medium. HU prevented cellular autolysis.

Autolysis↗

PubMed1997

Increased activation of the combination of 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine in the presence of hydroxyurea.

The intracellular phosphorylation of 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine was increased two- to threefold by the addition of hydroxyurea (HU) to the single drugs or to the two drugs in combination. The ratios of drug triphosphate to competing cellular deoxynucleoside triphosphate were increased two- to threefold for both 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine in the presence of HU. These HU-induced increases in 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine metabolism may further enhance the anti-human immunodeficiency virus activity of these two drugs.

Anti-HIV Agents↗

PubMed1999

Hydroxyurea enhances the activities of didanosine, 9-[2-(phosphonylmethoxy)ethyl]adenine, and 9-[2-(phosphonylmethoxy)propyl]adenine against drug-susceptible and drug-resistant human immunodeficiency virus isolates.

We assessed the effects of hydroxyurea (HU) at a concentration of 50 microM on the in vitro activities of 2',3'-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.

Adenine↗

PubMed2001

In vitro hydroxyurea decreases Th1 cell-mediated immunity.

Hydroxyurea (HU) is used in the treatment of hematologic disorders and is sometimes added to antiretroviral combination therapy to potentiate human immunodeficiency virus (HIV) suppression. However, HU has toxic effects on rapidly dividing cells, including the effectors of the immune response. To determine whether HU affects specific T-cell responses, we measured lymphocyte proliferation and cytokine production in response to microbial antigen and mitogen stimulation in the presence of added HU (10 to 1,000 microM). HU treatment of peripheral blood mononuclear cells obtained from HIV-infected patients and uninfected controls decreased lymphocyte proliferation and gamma interferon production compared with untreated cells. Interleukin-2 (IL-2) and IL-10 production was not affected by HU. The HU-mediated decrease of lymphocyte proliferation was similar in peripheral blood mononuclear cells from HIV-infected patients and from uninfected controls. The inhibitory effect of HU required continuous exposure to the drug and could be reverted by washing the drug out of the culture environment. These findings suggest that HU-containing therapeutic regimens might decrease Th1-cell-mediated immune responses in vivo.

Cell Division↗

PubMed1968

Electron microscopy of herpes simplex virus. 3. Effect of hydroxyurea.

The effect of hydroxyurea on the development of herpes virus is mediated through its inhibitory action on deoxyribonucleic acid (DNA) synthesis. Concentrations of the drug that suppress the production of infectious virus cause typical developmental anomalies: failure in formation of the normally dense cores or "complete" viral particles, and either faulty or no envelopment of viral capsids by membranes. The synthesis of viral capsids and virus-stimulated nuclear and cytoplasmic membranes, however, is not interrupted. Combining these results with those of time sequence experiments, the following hypotheses can be presented regarding viral development. Protein synthesis, which is characterized by capsids enclosing cores of low density, precedes DNA synthesis, which is characterized by the appearance of dense cores. Capsids with dense cores are selectively transported to the cytoplasm. Envelopment generally takes place as capsids pass from the nucleus to the cytoplasm. The process of envelopment is also selective, with the result that the majority of particles that have an envelope contain a full quota of DNA.

Culture Techniques↗

PubMed1983

Replication of herpes simplex virus type 1 on hydroxyurea-resistant baby hamster kidney cells.

Hydroxyurea-resistant (HUr) baby hamster kidney cells were isolated, subcloned, and characterized. One clonal line, which contained elevated levels of ribonucleotide reductase, lost its HU resistance during passage in the absence of the inhibitor, whereas another clonal line was stably resistant. The replication of herpes simplex virus type 1 on these cells was compared with that of the parvovirus minute virus of mice. Herpes simplex virus type 1 was found to be as sensitive to HU on both lines of HUr baby hamster kidney cells as it was on parental (HU-sensitive) cells, whereas parvovirus replication was about eight times more resistant on HUr baby hamster kidney cells compared with the parental cells. The results suggest that herpes simplex virus type 1 cannot use the cellular reductase and may code for its own.

Animals↗

PubMed1988

Vaccinia virus-encoded ribonucleotide reductase: sequence conservation of the gene for the small subunit and its amplification in hydroxyurea-resistant mutants.

The vaccinia virus gene that encodes the small subunit of ribonucleotide reductase was localized to the HindIII F fragment by using degenerate oligonucleotide probes. DNA sequencing revealed a leftward-reading open reading frame that predicted a protein of 37 kilodaltons whose amino acid sequence was much more homologous to the mouse and clam M2 sequences (approximately 80%) than to the corresponding herpesvirus (approximately 27%) or procaryotic (approximately 19%) gene products. Vaccinia virus mutants selected for the ability to grow in high concentrations of a specific inhibitor of ribonucleotide reductase, hydroxyurea, amplified the M2 gene and harbored tandem arrays (2 to 15 copies) of the gene within the HindIII F region. RNA isolated at early times after infection with wild-type virus and probed with an internal fragment of the M2 gene indicated one major (1.2 kilobases) and two minor (4.0 and 2.1 kilobases) transcripts. S1 nuclease analysis and primer extension experiments identified an RNA start site 12 nucleotides upstream of the putative initiation ATG codon.

Amino Acid Sequence↗

PubMed2004

The protein kinase Snf1 is required for tolerance to the ribonucleotide reductase inhibitor hydroxyurea.

The Snf1/AMP-activated kinases are involved in a wide range of stress responses in eukaryotic cells. We discovered a novel role for the Snf1 kinase in the cellular response to genotoxic stress in yeast. snf1 mutants are hypersensitive to hydroxyurea (HU), methyl-methane sulfonate, and cadmium, but they are not sensitive to several other genotoxic agents. HU inhibits ribonucleotide reductase (RNR), and deletion of SNF1 also increased the growth defects of an rnr4 ribonucleotide reductase mutant. The snf1 mutant has a functional checkpoint response to HU insofar as cells arrest division normally and derepress the transcription of RNR genes. The sensitivity of snf1 to HU or to RNR4 deletion may be due to posttranscriptional defects in RNR function or to defects in the repair of, and recovery from, stalled replication forks. The Mig3 repressor was identified as one target of Snf1 in this pathway. Genetic and biochemical analyses suggest that a weak kinase activity is sufficient to confer resistance to HU, whereas a high level of kinase activity is required for optimal growth on carbon sources other than glucose. Quantitative regulation of Snf1 kinase activity may contribute to the specificity of the effector responses that it controls.

Cadmium↗

PubMed2005

Loss of SOD1 and LYS7 sensitizes Saccharomyces cerevisiae to hydroxyurea and DNA damage agents and downregulates MEC1 pathway effectors.

Aerobic metabolism produces reactive oxygen species, including superoxide anions, which cause DNA damage unless removed by scavengers such as superoxide dismutases. We show that loss of the Cu,Zn-dependent superoxide dismutase, SOD1, or its copper chaperone, LYS7, confers oxygen-dependent sensitivity to replication arrest and DNA damage in Saccharomyces cerevisiae. We also find that sod1Delta strains, and to a lesser extent lys7Delta strains, when arrested with hydroxyurea (HU) show reduced induction of the MEC1 pathway effector Rnr3p and of Hug1p. The HU sensitivity of sod1Delta and lys7Delta strains is suppressed by overexpression of TKL1, a transketolase that generates NADPH, which balances redox in the cell and is required for ribonucleotide reductase activity. Our results suggest that the MEC1 pathway in sod1Delta mutant strains is sensitive to the altered cellular redox state due to increased superoxide anions and establish a new relationship between SOD1, LYS7, and the MEC1-mediated checkpoint response to replication arrest and DNA damage in S. cerevisiae.

Cell Cycle Proteins↗

PubMed1994

Pregnancy after treatment with hydroxyurea in a patient with primary thrombocythaemia and a history of recurrent abortion.

A 28 year old patient with primary thrombocythaemia, who had had two stillbirths in the third trimester, is reported. She was successfully treated with hydroxyurea and delivered a healthy 6lb boy by elective caesarean section. The ease with which this treatment can be given, its high level of tolerance among patients, and its low cost are likely to increase its use as a safe and effective treatment in pregnant patients with primary thrombocythaemia.

Abortion, Habitual↗