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 775 records · Page 43Linked to original sources

PubMed2006

Effects of hydroxyurea and aphidicolin on phosphorylation of ataxia telangiectasia mutated on Ser 1981 and histone H2AX on Ser 139 in relation to cell cycle phase and induction of apoptosis.

BACKGROUND: DNA replication stress often induces DNA damage. The antitumor drug hydroxyurea (HU), a potent inhibitor of ribonucleotide reductase that halts DNA replication through its effects on cellular deoxynucleotide pools, was shown to damage DNA inducing double-strand breaks (DSBs). Aphidicolin (APH), an inhibitor of alpha-like DNA polymerases, was also reported to cause DNA damage, but the evidence for induction of DSBs by APH is not straightforward. Histone H2AX is phosphorylated on Ser 139 in response to DSBs and one of the protein kinases that phosphorylate H2AX is ataxia telangiectasia mutated (ATM); activation of ATM is through its phosphorylation of Ser 1981. The present study was undertaken to reveal whether H2AX is phosphorylated in cells exposed to HU or APH and whether its phosphorylation is mediated by ATM. MATERIALS AND METHODS: HL-60 cells were treated in cultures with 0.1-5.0 mM HU or 1-4 muM APH for up to 5 h. Activation of ATM and H2AX phosphorylation was detected immunocytochemically using Ab specific to Ser1981-ATM or Ser 139-H2AX epitopes, respectively, concurrent with measurement of cellular DNA content. RESULTS: While exposure of cells to HU led to H2AX phosphorylation selectively during S phase and the cells progressing through the early portion of S (DI = 1.1-1.4) were more affected than late-S phase (DI = 1.6-1.9) cells, ATM was not activated by HU. In fact, the level of constitutive ("programmed") ATM phosphorylation was distinctly suppressed, in all phases of the cell cycle, at 0.1-5.0 mM HU. Cells' exposure to APH also resulted in H2AX phosphorylation at Ser139 with no evidence of ATM activation, and as in the case of HU, the early-S cells were more affected than the late-S phase cells. The rise in frequency of apoptotic cells became apparent after 2 h of exposure to HU or APH, and all apoptotic cells had markedly elevated levels of both H2AX-Ser139 and ATM-Ser1981 phosphorylation. CONCLUSIONS: The lack of correlation between H2AX phosphorylation and ATM activation indicates that protein kinase(s) other than ATM (ATR and/or DNA-dependent protein kinase) are activated by DSBs induced by replication stress. Interestingly, HU inhibits the constitutive ("programmed") level of ATM phosphorylation in untreated cells. However, DNA fragmentation during apoptosis activates ATM and dramatically increases level of H2AX phosphorylation.

Aphidicolin↗

PubMed2005

Laboratory variability does not preclude identification of biological functions impacted by hydroxyurea.

The multi-lab International Life Sciences Institute (ILSI) project on the application of genomics to risk assessment offered the unique opportunity to investigate the influence of variability within and between laboratories on identifying biologically relevant gene expression changes. We assessed the gene expression profiles of mouse lymphoma L5178Y cells treated with hydroxyurea (HU) in three independent studies from two different laboratories, Sanofi Aventis and Procter and Gamble. Cells were dosed for 4 hr and harvested immediately at the end of the treatment or after a 20-hr recovery period. Cytotoxicity and genotoxicity were evaluated by standard assays. Statistical analysis of these data revealed that, while gene expression responses to HU treatment were markedly different at 4 hr vs. 24 hr, there was otherwise a consistent pattern of dose-response across the three studies. Therefore, the studies were merged and each time point was evaluated separately. At 4 hr, we identified 173 (P < 0.0001) dose-responsive genes with a common trend in all three studies. These were mainly associated with the cell cycle, DNA repair and DNA metabolism, and in particular, the intra-S and G2/M phase checkpoints. At 24 hr, we identified 434 dose-responsive genes common across studies. These genes were involved in lymphocyte-specific activities and the activation of apoptosis via the caspase cascade. Our results show that despite inter-laboratory variability, combining the three studies in a single statistical analysis identifies more significantly-modulated genes than in any of the individual studies, due to improved statistical sensitivity. The genes identified in our study provide information that is relevant to HU biology.

Animals↗

PubMed2007

Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea.

Recently, it was shown that MYCN amplified cells spontaneously expulse extrachromosomally amplified gene copies by micronuclei formation. Furthermore, it was shown that these cells lose their malignant phenotype and start to age. We tested whether it is possible to encourage neuroblastoma tumor cells to enter the senescence pathway by low concentrations of the micronuclei-inducing drug hydroxyurea (HU). We studied the effect of HU on 12 neuroblastoma cell lines with extra- or intrachromosomally amplified MYCN copies and without amplification. Two extrachromosomally amplified neuroblastoma cell lines (with double minutes) were investigated in detail. Already after 3 weeks of HU treatment, the BrdU uptake dropped to 25% of the starting cells. After 4 weeks, enlarged and flattened cells (F-cells) and increased granularity in the majority of cells were observed. A drastic reduction of the MYCN copy number-down to one copy per cell-associated with CD44 and MHCI upregulation in up to 100% of the HU treated neuroblastoma cells was found after 5-8 weeks. Telomere length was reduced to half the length within 8 weeks of HU treatment, and telomerase activity was not detectable at this time, while being strongly expressed at the beginning. All these features and the expression of senescence-associated-beta-galactosidase (SA-beta-GAL) in up to 100% of the cells support the hypothesis that these cells entered the senescence pathway. Thus, low-dose HU is a potent senescence elicitor for tumor cells with gene amplification, possibly representing an attractive additional strategy for treatment of this subset of tumors.

Antineoplastic Agents↗

PubMed2007

Phase II clinical trial of parenteral hydroxyurea and hyper-fractionated, accelerated external beam radiation therapy in patients with advanced squamous cell carcinoma of the head and neck: toxicity and efficacy with continuous ribonucleoside reductase inhibition.

BACKGROUND: Almost all concurrent chemoradiation regimens for head and neck are platinum based; however, cisplatin is associated with severe renal, oto-, and neurotoxicity. Hydroxyurea (HU) has been associated with fewer irreversible toxicities. We obtained HU in parenteral form to be administered continually during the radiation treatment. Intravenous HU promised better pharmacokinetics and cell cycle blockade. METHODS: Participants had biopsy-proven, untreated squamous cell carcinoma of the oral cavity, oropharynx (stage IV) and hypopharynx (stages II-IV). Radiation therapy consisted initially of 74.4 Gy administered in twice daily 1.2-Gy fractions. After 20 patients, the radiation dose was reduced to 60.0 Gy, and another 16 patients were enrolled. RESULTS: Patients received HU by Continuous Ambulatory Drug Delivery (CADD) pump on a daily x5 schedule during radiation therapy. Because of persistent long-term dysphagia, after 20 patients, the dose of external beam radiation therapy was reduced from 74 to 60 Gy, and the duration of concurrent HU was correspondingly reduced. The new regimen was much better tolerated. The median survival for the group as a whole was 30 months. Within this small study, there were no significant differences in survival, regional control, or local control between the 2 groups. CONCLUSIONS: Lower doses of concurrent parenteral HU and hyper-fractionated radiation therapy are tolerable and promising.

Aged↗

PubMed2005

Der(8)t(1;8) in myeloblastic transformation of ET with hydroxyurea as the sole prior treatment.

We described a patient with ET that evolved into MF and then subsequently developed myeloblastic transformation. A novel derivative chromosome der(8)t(1;8) was identified in the AML phase. The only prior treatment had been hydroxyurea. We hypothesized that AML in this case resulted from a complex pre-disposition by the natural progression of ET, prolonged use of HU, and the prior evolution into MF. The leukemogenic risk of HU is critically appraised.

Cell Transformation, Neoplastic↗

PubMed1979

Enhancement of host cell reactivation of ultraviolet-irradiated Herpes simplex virus by caffeine, hydroxyurea and 5-bromodeoxyuridine.

Enhancement of host cell reactivation (HCR) of ultraviolet (UV)-irradiated herpes simplex virus (HSV) was demonstrated in cell cultures pretreated with caffeine, hydroxyurea, or 5-bromodeoxyuridine (BrdUrd). The effect of caffeine on HCR was shown to depend on the time of drug treatment with respect to infection. In cultures treated with caffeine during the course of virus replication, the infectivity of irradiated HSV was reduced about nine-fold, while cultures pretreated with the drug before infection showed an increase in infectivity. The extent of HCR enhancement depended on the time interval between treatment with caffeine and infection, drug concentration, and the UV irradiation dose to which HSV was exposed. Magnitude of enhancement of HCR by caffeine differed in various cell species. The results suggest that enhanced HCR of UV-irradiated HSV by DNA antimetabolities is associated with DNA repair activated in consequence of cell DNA damage.

Animals↗

PubMed1986

Enhancement of experimental metastasis by pretreatment of tumour cells with hydroxyurea.

The effect of treatment with hydroxyurea (HU), on subsequent experimental metastasis formation by cells of 3 murine melanoma lines has been examined. In vitro treatment of B16-F1, B16-F10 and K-1735-clone 19 cells with 0.1 mM or 0.3 mM HU, followed by a period of recovery in drug-free medium, resulted in a significant increase in the number of lung nodules formed in syngeneic mice following i.v. injection of the cells. The maximum effect obtained was observed when cells were injected 6 hr after removal of HU and it occurred in spite of the cytotoxicity of the doses used. Six hours after release from treatment with 0.3 mM HU cells were synchronized in the G2 phase of the cell cycle but the consequent increase in cell volume was not responsible for increased metastasis through enhancement of tumour-cell arrest, since lodgement of 51Cr-labelled, HU-treated cells was no greater than that of control cells. The results obtained suggest that the chemotherapeutic agent HU may facilitate tumour progression via a direct action on neoplastic cells.

Animals↗

PubMed2003

Reticulocyte parameters and hemoglobin F production in sickle cell disease patients undergoing hydroxyurea therapy.

Hemoglobin F (HbF) is an effective inhibitor of HbS polymerization. Hydroxyurea (HU) is used to increase HbF synthesis and improve the clinical course of sickle cell disease (SCD) patients. We studied a series of laboratory parameters concerning HbF production and reticulocyte response, and compared data between two groups: 1) 13 SCD patients treated with HU, and 2) 33 untreated SCD patients. Higher values of Hb concentration, mean cell volume (MCV), mean cell hemoglobin (MCH), mean reticulocyte volume (MRV), HbF concentration, percentage of F-cells, and amount of HbF/F-cells were observed in the treated group of patients. There was no correlation between Hb and HbF elevations. The reticulocyte count, immature reticulocyte count, mean fluorescence index (MFI), and neutrophil count were significantly lower in treated patients. Taken together, these findings suggest that a decreased hemolytic process occurred in patients undergoing HU treatment. There was a significant correlation between MCV and HbF, between MRV and HbF, and between MRV and F-cell in patients taking HU. These data indicate that macroreticulocytes correspond to F-reticulocytes, and that an increase in MRV in SCD patients using HU may be an indirect signal of F-cell production. The concentration of HbF/F-cells was higher in patients treated with HU, but this increase apparently was independent of F-cell production. Reticulocyte (RTC) parameters, as assessed by hematological analyzers, may be useful for following erythropoietic changes in patients receiving HU, and can indirectly indicate HbF and F-cell production induced by HU therapy.

Adult↗

PubMed2003

Contrasting effects of hydroxyurea on cell growth and reduction in Epstein-Barr virus genomes in EBV-infected epithelioid cell lines vs Burkitt's lymphoma cell lines.

Eliminating Epstein-Barr virus (EBV) genomes from infected cells is an intriguing theoretical strategy in therapy for EBV-associated malignant diseases. Respective patterns were characterized for hydroxyurea (HU)-promoted loss of EBV genomes from EBV-infected epithelioid cell lines derived from the noncancerous portion of gastric carcinoma tissues and Burkitt's lymphoma (BL) cell lines. Epithelioid cell lines GT38 and PN were less sensitivity to HU than BL cell lines Akata, Raji, and Daudi in terms of cell growth inhibition and cell cycle arrest. On passage in medium with 50 microM HU, the fraction of EBV nuclear antigen (EBNA)-positive cells was reduced substantially in the BL cell lines, but only slightly in the epithelioid cell lines. EBV DNA was reduced in Akata, Raji, and Daudi cells upon passage in 50 microM HU by 95%, 70%, and 50%, respectively, but by only 10% in GT38 cells, in which EBV DNA reduction was enhanced at increased concentrations of HU. This indicates that EBV genome is more easily lost from BL cell lines than from epithelioid cell lines upon culturing in HU. These findings support the view that the elimination of EBV could be therapeutically effective in EBV-associated BL by HU.

Burkitt Lymphoma↗

PubMed1975

Treatment of disseminated cancer by intravenous hydroxyurea and autogenous bone-marrow transplants: experience with 35 patients.

Massive doses of hydroxyurea (Hydrea) were given to 35 patients suffering from different cancers. Protection to the hematopoietic system was obtained by autogenous marrow transfusions. The clinical response obtained was not considered superior to the results obtained by administering the drug orally over a prolonged period. The described technique is safe and relatively atraumatic, and it may be advisable to administer a large priming dose by this technique to be followed by smaller maintenance doses of a given anticancer chemotherapeutic agent.

Bone Marrow Cells↗

PubMed1976

Cell kill kinetics with hydroxyurea.

The effects of various concentrations of hydroxyurea (HU) on a human lymphoid cell line in exponential growth phase have been studied using a combination of methods, including determination of the total and viable cell counts; the cells relative DNA content, measured in a flow microfluorimeter after staining with a fluorescent Feulgen technique; the mitotic index; and the percentage of cells incorporating thymidine-3H (TdR-3H) during brief and continuous exposure to the isotope both in the presence and absence of colcemid. A significant redistribution of the cells in the various phases of the cell cycle occurred during the first 24 hr of continuous treatment with 10(-3) M and 10(-2) M HU as follows: (1) division of cells in G2; (2) depletion of mid and late S phase cells due to early cell death; (3) movement of most G1 cells at a normal rate into early S phase where they accumulate; and (4) arrest of the remaining cells in G1, which represented the surviving population after treatment for 96 hr or longer. After removal of the drug, the cell fraction blocked in early S phase progressed semisynchronously through S, but many of the cells were unable to complete division. Their capacity to recover depended on the drug concentration and duration of exposure, but in general the cellular injury caused by HU was more reversible than that caused by "equivalent" concentrations of arabinosylcytosine.

Cell Count↗

PubMed2002

Hydroxyurea-induced partial mushroom body ablation in the honeybee Apis mellifera: volumetric analysis and quantitative protein determination.

Hydroxyurea (HU) treatment of first instar honeybee larvae was previously shown to cause mushroom body (MB) ablations. Predominantly, either one or both median MB subunits were ablated. This prompted us to analyze the effects of asymmetrical or symmetrical HU-induced MB ablation on both the morphology of the brain and on the level of three proteins (synapsin, PKA RII, and PKC), which are considered to play a role in synaptic plasticity, learning, and memory. In brains with one median MB subunit missing the volume of the overall MB calyx neuropil in the lesioned side was diminished by 35%. This strong reduction occurred although the remaining lateral MB calyx of the lesioned brain side was found to be significantly larger than that of the intact side. Accordingly, in brains with both median MB subunits missing the size of the remaining lateral calyces increased. The various types of MB ablation differentially affected the amounts of synapsin, PKA RII, and PKC expressed in the central brain. In animals with bilateral and thus symmetrical MB ablation (both median calyces ablated) the protein amount was found to be similar to that in control animals. However, unilateral MB ablation causes an increase in the amounts of the tested proteins in the intact brain side, while the levels in the ablated side were the same as in control animals. These findings not only show that HU-induced ablation of MB subunits is accompanied by volume changes and by changes in protein expression, but also suggest that these processes are highly regulated between the brain sides. The latter is of general importance in understanding the potential contribution of the MB subunits to learning and memory and their interaction between the brain sides.

Animals↗

PubMed2002

Hydroxyurea-induced partial mushroom body ablation does not affect acquisition and retention of olfactory differential conditioning in honeybees.

The mushroom bodies (MBs), a paired structure in the insect brain, play a major role in storing and retrieving olfactory memories. We tested whether olfactory learning and odor processing is impaired in honeybees in which MB subunits were partially ablated. Using hydroxyurea (HU) to selectively kill proliferating cells, we created honeybees with varying degrees of MB lesions. Three-dimensional reconstructions of brains were generated to analyze the drug-induced morphological changes. These reconstructions show that, with few exceptions, only the MBs were affected by the drug, while other brain areas remained morphometrically intact. Typically, lesions affected only the MB in one hemisphere of the brain. To preclude HU-induced physiologic deficits in the antennal lobe (AL) affecting olfactory learning, we measured the responses to odors in the AL using an in vivo calcium imaging approach. The response patterns did not differ between the AL of intact versus ablated brain sides within respective specimens. We, therefore, carried out side-specific classical discriminative olfactory conditioning of the proboscis extension reflex (PER) with control bees and with HU-treated bees with or without MB ablations. All experimental groups learned equally to discriminate and respond to a rewarded (CS+) but not to an unrewarded (CS-) conditioned stimulus during acquisition and retention tests. Thus, our results indicate that partial MB lesions do not affect this form of elemental olfactory learning.

Animals↗

PubMed1986

Adult-specific neurons in the nervous system of the moth, Manduca sexta: selective chemical ablation using hydroxyurea.

The segmental ganglia of adults of the moth, Manduca sexta, are constructed both from remodeled larval neurons and from adult-specific cells. The latter are produced by identified stem cells (neuroblasts) during larval life and then differentiate to form functional neurons during metamorphosis. The mitotic activity of the larval neuroblasts could be irreversibly blocked by the DNA-synthesis inhibitor hydroxyurea (HU). Treatment on day 1 of the third larval stage resulted in 80-90% of the neuroblasts being blocked before they produced any progeny while leaving the functional larval neurons unaffected. Treated larvae finished growth, underwent metamorphosis, and produced an adult CNS that contained the normal set of remodeled larval neurons but lacked most of the new adult-specific cells. When HU treatment was delayed until the start of the fourth or fifth larval stage, the neuroblasts produced the early portions of their respective lineages before they were blocked. The immature neurons that were generated prior to treatment survived to contribute adult-specific neurons to the moth CNS, but the remainder of each lineage was missing. This technique therefore enables one to produce adult nervous systems containing the basic set of remodeled larval cells plus defined sets of adult-specific neurons.

Animals↗

PubMed2006

Hydroxyurea therapy lowers TCD velocities in children with sickle cell disease.

INTRODUCTION: Hydroxyurea (HU) improves hematologic parameters and decreases adverse events in patients with sickle cell disease (SCD). HU has been proposed as an alternative to chronic transfusions for secondary stroke prevention. Transcranial doppler (TCD) is an accepted method of stroke risk stratification in patients with SCD. We sought to determine if HU affects TCD velocities in children with SCD. METHODS: A cohort of 24 children with HbSS with a baseline TCDi prior to HU and a follow-up after at least 6 months of therapy was analyzed. Twenty-four age-matched children with HbSS formed the control group. Differences in hematologic parameters before and after HU therapy were evaluated. RESULTS: TCDi velocities decreased in the HU-treated patients. The adjusted mean change in TCDi velocities was -13.0 cm/sec (95% CI -20.19, -5.92) in the HU-treated group and +4.72 cm/sec (95% CI -3.24, 12.69) in the controls. Changes in TCDi between the two groups were statistically significant (P < 0.001). Changes in hematologic parameters were not predictive of changes in TCDi velocities in the treated patients. Four out of five patients with TCDi velocities >170 cm/sec had normalization of TCDi velocities on HU. Mean change was -34.75 cm/sec in this subgroup. No patients experienced cerebrovascular accidents (CVA) while on HU. CONCLUSIONS: HU-treated patients experienced statistically significant decreases in TCDi velocities compared to age-matched controls. Changes in hematologic parameters were not predictive of changes in TCDi velocities in the treated group. The decrease in TCDi velocities is not a consequence of changes in hematologic values in patients treated with HU.

Adolescent↗

PubMed1999

In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-HIV-1 activity.

Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [HU]) have been proposed as a new therapeutic strategy for the treatment of HIV type-1 (HIV-1) infection. However, HU use may be limited by the frequent development of hematopoietic toxicity. We report here short-term hematopoietic toxicity in mice receiving HU when compared to either of two more potent enzyme inhibitors, didox (DX) and trimidox (TX). High dose HU, DX, and TX monotherapy (500, 460, and 220 mg/kg/day respectively) was administered by daily i.p. injection (Monday-Friday) to C57BL/6 mice for 10 weeks. Effects on hematopoiesis were established by quantitating peripheral blood indices (hematocrit, hemoglobin, mean corpuscular volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, RBC, and WBC) and numbers of colony-forming units-granulocyte-macrophage (CFU-GM) and BFU-E from bone marrow and spleen. HU produced rapid induction of a macrocytic hypochromic anemia and altered white blood cell kinetics associated with myelosuppression defined as reduced marrow organ cellularity and induction of splenic extramedullary hematopoiesis. Compared to HU, TX and DX induced fewer changes in peripheral blood indices and CFU-GM and BFU-E per hematopoietic organ. In vitro human and murine marrow CFU-GM and BFU-E colony formations were assayed in the presence of dose escalation HU, DX, or TX (0, 1, 10, 50, 100, and 200 microM). HU inhibited colony formation more than either DX or TX. These in vivo and in vitro studies suggest that novel ribonucleotide reductase inhibitors TX and DX may provide an effective alternative to HU in HIV-1 therapy because they demonstrate reduced hematopoietic toxicity.

Acquired Immunodeficiency Syndrome↗

PubMed1978

Investigation of the effect of hydroxyurea on the cell cycle and the development of necrosis in the embryonic CNS of mice.

On day 10 of gestation pregnant mice (strain NMRI) were given an intravenous injection of 500 mg/kg Hydroxyurea (HU). Simultaneously either 5 muCi/g or 10 muCi/g 3H-thymidine (3H-Tdr; specific activity 5Ci/mmol) was administered to the animals. At various times after treatment embryos and electron microscopy. Two hours after administration of HU condensations of the chromatin structure could be detected electron microscopically in some cells. Thirty minutes later the nucleolus became smaller and denser, the cytoplasm shrank, and the cell organelles moved closer together. Three hours after application of the drug break-down of the involved cells set in. As in the autoradiograms about 98% of the counted necroses were labelled, and since labelled thymidine is almost exclusively incorporated during the S-phase, it can be stated the HU influences only metabolic processes which take place during the S-phase. From the morphological findings it can be concluded that in the case of the S-phase-specific metabolic pathway, which is influenced by HU, we are primarily dealing with DNA synthesis.

Animals↗

PubMed1980

Cell cycle phase specificity of hydroxyurea and its effects on the cell kinetics in embryonic spinal cord.

Pregnant mice (NMRI) received an intravenous injection of 500 mg/kg of hydroxyurea (HU) on day 10 of gestation. The animals were killed 1, 1.5, 2, 2.5, 4, 6, 8 or 10 h after application of the drug and the embryos removed. Forty-five min. prior to sacrifice, the animals were given an intraperitoneal injection of 5 microCi/g 3H-thymidine (specific activity 5 Ci/mmol). From autoradiographs of the embryos the percentage of mitoses, necroses and labelled cells of the spinal cord was determined at the various time intervals. It was observed that HU inhibited DNA-synthesis in all S-phase cells for more than 4 hours. All cells damaged by HU did not start DNA-synthesis again and became necrotic. Only cells entering the S-phase after the influence of HU could replicate their DNA in a normal manner. It is assumed that HU possibly blocks cells in the G2-phase and in the mitosis for a certain period of time.

Animals↗