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PubMed1987

Gene for M1 subunit of ribonucleotide reductase is amplified in hydroxyurea-resistant hamster cells.

The hydroxyurea-resistant Chinese hamster cell line 600H has been shown to have greatly elevated quantities of ribonucleotide reductase. This increase in enzyme activity is due to an increased level of both the M1 and M2 subunit activities. The M1 subunit has been purified from the 600H cell line and shown to consist of a series of six protein spots with apparent molecular weights of 88,000 daltons, but with varying isoelectric points in the range of pH 6.5-7.0. Western blot analyses with antisera against the M1 and M2 proteins indicated that both subunit proteins are present in elevated quantities in the 600H cell line when compared to the wild-type V79 cell line. Southern blot analyses with genomic DNA from the series of stepwise-selected hydroxyurea-resistant cell lines leading to 600H showed that, in latter steps of selection, genomic sequences homologous to a mouse M1 cDNA have undergone a fivefold amplification. This was accompanied by a four- to eightfold increase in the single M1 homologous mRNA.

Animals↗
PubMed1980

Scanning electron microscopy of cells from hydroxyurea-arrested blastulae of Xenopus laevis.

Cells from Xenopus embryos blocked at the blastula stage by treatment with hydroxyurea have been isolated and cultured in vitro. The morphology of these cells has been compared with that of cells from normal embryos using scanning electron microscopy. Cells from such hydroxyurea-blocked embryos do not show the features, or changes in features, in culture shown by cells from normal embryos.

Animals↗
PubMed1993

Pharmacological modification of hemoglobin F expression in sickle cell anemia: an update on hydroxyurea studies.

The most studied pharmacological intervention in sickle cell anemia aiming at elevating HbF expression is the use of hydroxyurea. At the present time the experience has been that after 1 year of treatment with maximum tolerated doses (MTD) all patients showed increases of percent HbF, with a mean of 15% HbF, without apparent side effects besides the reversible ones observed during the process of attaining the MTD. The question of efficacy is presently being investigated by a multicenter placebo controlled double blind clinical trial that involves more than 20 sites. The goal of the study is to determine if hydroxyurea can decrease the incidence of painful crises by 50%. Results of this study are not expected before the end of 1993.

Anemia, Sickle Cell↗
PubMedDate not supplied

Hematological responses to hydroxyurea therapy in multitransfused thalassemic children.

Fifteen multi-transfused thalassemic children between 3-6 years of age (seven boys and eight girls) were administered hydroxyurea for 5 days and three such cycles were repeated at 15 days interval. Rise in hemoglobin levels was observed in 13, 8 and 7 cases, while rise in mean hemoglobin F was seen in 8, 11 and 10 cases following 1st, 2nd and 3rd course of hydroxyurea therapy respectively. Rise in hemoglobin level was associated with transient rise in fetal hemoglobin level. Though the changes in mean hemoglobin levels and hemoglobin F levels were statistically insignificant, a definite trend of rise in hemoglobin and hemoglobin F was observed.

Blood Transfusion↗
PubMed2003

Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors.

PURPOSE: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. METHODS: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m(2) by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m(2) CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 microg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. RESULTS: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. CONCLUSIONS: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

Adult↗
PubMed2006

Gottron's papules-like eruption developing under hydroxyurea therapy.

A 57-year-old white female developed a Gottron's papules (GP)-like eruption, without any of the other clinical or laboratory signs of dermatomyositis (DM). She was under hydroxyurea treatment for chronic myeloid leukemia at the time. Skin biopsy was compatible with seborrheic keratosis. Conditions presenting with GP but unrelated to DM are reviewed, with emphasis on hydroxyurea-induced skin lesions.

Biopsy↗
PubMed2005

Role of the iron mobilization and oxidative stress regulons in the genomic response of yeast to hydroxyurea.

Hydroxyurea (HU) is a specific inhibitor of ribonucleotide reductase and thus impairs dNTP synthesis and DNA replication. The long-term transcriptional response of yeast cells to hydroxyurea was investigated using DNA microarrays containing all yeast coding sequences. We show that the redox-responsive Yap regulon and the iron-mobilization Aft regulon are activated in yeast cells treated with HU. Yap1 accumulates in the nucleus in response to HU, but HU activation of the Yap regulon was only partially dependent on Yap1 and yap1Delta mutants were not hypersensitive to HU. In contrast, deletion of the AFT1 and AFT2 transcription factor genes blocked the HU activation of a subset of the Aft regulon and the aft1Delta aft2Delta double mutant was hypersensitive to HU in an iron-suppressible manner. These results highlight the importance of the redox and iron mobilization regulons in the cellular response to HU.

Drug Resistance, Fungal↗
PubMed2006

Phosphorylation of H2AX histones in response to double-strand breaks and induction of premature chromatin condensation in hydroxyurea-treated root meristem cells of Raphanus sativus, Vicia faba, and Allium porrum.

Histone H2A variant H2AX is rapidly phosphorylated on the induction of DNA double-strand breaks by ionizing radiation and hydroxyurea-mediated replication arrest, resulting in the formation of gamma-H2AX foci along megabase chromatin domains nearby the sites of incurred DNA damage. In an attempt to establish a relationship between species-specific nuclear architecture and H2AX phosphorylation in S/G(2) phase-arrested root meristem cells, immunocytochemical comparisons using an antibody raised against human gamma-H2AX were made among three plants differing with respect to DNA contents: Allium porrum, representing a reticulate type of DNA package, Vicia faba, having semireticulate cell nuclei, and Raphanus sativus, characterised by a chromocentric type of chromatin. Another approach was aimed at determining possible correlations between the extent of hydroxyurea-induced phosphorylation of H2AX histones and the quantities of root meristem cells induced by caffeine to enter aberrant mitotic division (premature chromosome condensation). It was concluded that the higher-order structure of chromatin may contribute to the accessibility of molecular factors engaged in the recognition and repair of genetic lesions. Consequently, in contrast to A. porrum and V. faba, a diffuse chromatin in chromocentric cell nuclei of R. sativus may become more vulnerable both to generate DNA double-strand breaks and to recruit molecular elements needed to arrange the cell cycle checkpoint functions, and thus, more resistant to factors which allow the cells to enter premature chromosome condensation spontaneously. On the other hand, however, caffeine-mediated overriding of the S-M checkpoint control system resulted in the typical appearance of premature chromosome condensation, irrespective of the genomic content of DNA.

Antineoplastic Agents↗
PubMed1975

Eosinophilic leukemia. Remission with vincristine and hydroxyurea.

A 40 year old man with eosinophilic leukemia was treated with a variety of chemotherapeutic agents. A long-term remission, unusual for eosinophilic leukemia, was maintained with chronic hydroxyurea therapy after induction with vincristine. Hydroxyurea and vincristine may offer an effective mode of therapy for this disease.

Adult↗
PubMed1991

Use of hydroxyurea in chronic myeloid leukemia during pregnancy: a case report.

The concomitant occurrence of pregnancy and chronic myeloid leukemia is uncommon. The use of hydroxyurea in chronic myeloid leukemia during pregnancy is unknown. We report on a patient with chronic myeloid leukemia in whom hydroxyurea was used during pregnancy with a successful outcome for both mother and fetus.

Adult↗
PubMed1985

Uridine diphosphate reductase of Ehrlich ascites tumor is insensitive to hydroxyurea.

Uridine diphosphate (UDP) reductase was isolated in the supernatant fraction obtained after the acidification of the cytosol of Ehrlich ascites tumor cells, and was found insensitive to 10 mM hydroxyurea. However, cytidine diphosphate (CDP) reductase, being separated concurrently in the precipitate fraction, was readily inhibited. In the cytosol fraction of either Ehrlich ascites tumor, Yoshida ascites sarcoma or regenerating rat liver after partial hepatectomy, UDP reduction activity, in contrast to CDP reduction activity, is not sensitive to hydroxyurea.

Animals↗
PubMed1982

Effect of hydroxyurea and 5-fluorodeoxyuridine on deoxyribonucleoside triphosphate pools early in phytohemagglutinin-stimulated human lymphocytes.

The induction of deoxyribonucleoside triphosphate pools was studied in phytohemagglutinin-stimulated human lymphocytes in the presence of metabolic inhibitors. The dATP pool was completely inhibited in cells treated with hydroxyurea, in contrast to the dTTP pool. However, 1-formyl-isoquinoline thiosemicarbazone inhibited the formation of these pools equally. During approximately 3 hr of treatment of stimulated cells with hydroxyurea, the dATP, dGTP and dCTP pools were depleted to the base levels observed in the cells before the pools were induced. The base level of the dTTP pool was achieved only in the presence of 5-fluorodeoxyuridine, but the inhibition was completely prevented by addition of thymidine. It is suggested that, when resting lymphocytes were stimulated to enter the growth cycle, the formation of deoxyribonucleoside triphosphates in the early transformation was due to the de novo pathway.

DNA↗
PubMed1988

Induction of HL-60 monocytic cell differentiation promoted by a perturbation of DNA synthesis: hydroxyurea promotes action of TPA.

Control of terminal cell differentiation was studied using the human promyelocytic leukemia cell line, HL-60. HL-60 cells are known to undergo terminal monocytic differentiation when continuously exposed to 1.6 nM tetradecanoylphorbol acetate (TPA). The dose-response relationship between TPA concentration and induced differentiation is relatively steep. TPA (1.1 nM) induces little G1/0 specific growth inhibition or phenotypic differentiation. In contrast, pretreating the cells with a pulse exposure to hydroxyurea promotes their capability to terminally differentiate in response to TPA. Initially exponentially proliferating cells exposed for 20 h, approximately one doubling time, to 0.3 mM hydroxyurea, a subcytotoxic dose, underwent rapid G1/0 specific growth arrest and cell differentiation in response to subsequent exposure to 1.1 nM TPA. The extent of terminal differentiation was comparable to that induced by 1.6 nM TPA. The results support the hypothesis that early events in induction of terminal HL-60 cell differentiation depend on an S phase-specific process which may involve gene amplification.

Cell Differentiation↗
PubMedDate not supplied

Deoxyribonucleoside triphosphate pools in Neurospora crassa: effects of histidine and hydroxyurea.

An effective HPLC method for detecting deoxyribonucleoside triphosphates in hyphae from the fungus Neurospora crassa has been developed. In rapidly growing cells the nucleotide levels vary from 11.8 pmoles/micrograms DNA for dGTP to 24.2 pmoles/micrograms DNA for dTTP. These levels fall by approximately one half in stationary-phase cultures but the ratio of each pool to dGTP remains the same. The dNTP pools in conidia are at least 5-fold lower than in rapidly growing cells. The pool sizes are the same in static and shaking cultures. When the ribonucleotide reductase inhibitor, hydroxyurea (30 mM), is added to rapidly growing cultures, DNA synthesis is stopped and the dGTP pool is reduced by 39%, while the size of the other pools remains the same. In the presence of 11 mM histidine, DNA synthesis is also stopped and the size of the dGTP pool reduced by 46% while the deoxypyrimidine pools are somewhat increased. This suggests that the toxicity of excess histidine in Neurospora may be due to its ability to interact with the ribonucleotide reductase, inactivating the enzyme. Histidine may react with the free radical at the active site, as does hydroxyurea.

Chromatography, High Pressure Liquid↗
PubMed1988

Simultaneous detection of DNA strand breaks and unscheduled DNA synthesis in mutagen-treated human lymphocytes in the absence of hydroxyurea.

Human lymphocytes in the quiescent state were exposed to UVC radiation. After irradiation the cells were allowed to repair for various times in the presence of [3H]thymidine or [3H]deoxycytidine in the culture medium. Hydroxyurea was not used to suppress semiconservative DNA replication in the small number of growing cells. After incubation DNA strand breaks were detected by the DNA-unwinding method and the amount of 3H incorporation in DNA was measured by liquid scintillation counting. The results show that the yield of DNA strand breaks and the amount of unscheduled DNA synthesis (UDS) can be measured from the same lymphocyte sample. A low background 3H incorporation in untreated cells could be achieved even in the absence of hydroxyurea. This requires, however, that 3H incorporation is measured only in the double-stranded DNA and that [3H]dCyd is used instead of [3H]dThd as the labelled deoxynucleoside.

Chromatography↗
PubMed1990

Effects of cytosine arabinoside and hydroxyurea on the synthesis of deoxyribonucleotides and DNA replication in L1210 cells.

Experiments were carried out in L1210 cells to examine the importance of 'substrate cycles' in regulating the intracellular levels of deoxyribonucleoside 5'-triphosphate. L1210 cells were incubated with [14C]cytidine or [14C]adenosine in the presence and absence of hydroxyurea or cytosine arabinoside (araC). These incubations were carried out for either 30 or 120 min. Inhibition of ribonucleotide reductase by hydroxyurea resulted in the blockage of the flux of ribonucleotides to deoxyribonucleotides (greater than 90%) as expected. When DNA synthesis was inhibited with araC, there was a marked decrease in the incorporation of [14C]cytidine or [14C]adenosine into DNA as deoxyribonucleotides. However, there was not a corresponding increase in the deoxyribonucleotide levels in the acid-soluble fraction or deoxyribonucleosides in the culture medium. AraC treatment decreased the total formation of deoxyribonucleotides. These data indicate that L1210 cells do not regulate the intracellular pools of dNTPs via 'substrate cycles' which involve activation of phosphatases when DNA synthesis is blocked or activation of kinases when ribonucleotide reductase is inhibited.

Adenosine↗
PubMed1977

Hydroxyurea in stage D carcinoma of prostate.

Thirty patients with histologically proved metastatic prostatic adenocarcinoma Stage D were treated with a single oral dose of 80 mg. per Kg. hydroxyurea every third day (based on ideal or actual weight, whichever is less) and 12 mg. chlorotrianisene per day. Toxicity was mild. The most common manifestations were nausea, occasional vomiting, and leukopenia. A definite attempt was made to depress the white blood count to approximately 2,000 cells per cu. mm. Hydroxyurea was not discontinued unless the white blood count decreased to less than 2,000 cells per cu. mm., after which a single dose was usually omitted. Omission of a single dose would allow the white blood count to return promptly to more than 2,000 cells per cu. mm. Objective tumor regression was demonstrated in 15 of the 30 patients, and most patients had a definite improvement in the quality of life.

Aged↗