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PubMed2000

Reduction of the clinical severity of sickle cell/beta-thalassemia with hydroxyurea: the experience of a single center in Greece.

The use of hydroxyurea for the prevention of sickle cell crises in patients with homozygous HbS disease is now well established. The beneficial effects of this compound stem from (a) selective enrichment of red cells containing an increased amount of fetal hemoglobin, which inhibits HbS polymerization, and (b) a decrease of leukocytes, platelets, and reticulocytes, which significantly limits their adherence to the vascular wall. We report the results of a clinical trial of hydroxyurea on 55 Greek-origin patients with sickle cell/beta-thalassemia and 14 patients with homozygous HbS disease who have been treated with hydroxyurea for several years. Such patients have a higher probability to benefit from hydroxyurea therapy, since in addition to its antisickling effect, the increase of gamma-chain synthesis is expected to diminish the deleterious effects of the unbound alpha-globin chains. Selection of patients and monitoring throughout the whole trial were done by the same clinicians. Quantitative expression of the clinical condition was done using a system scoring several outcome parameters. For a period of 52 months prior to starting treatment, the total score of severity for 59 evaluable patients was 1182 points (3068 patient-weeks), while for the 12,018 patient-weeks of the trial this parameter fell to only 82 points. Other observations of interest include the significant improvement of a group of patients with hepatic cholestasis, the development of leg ulcers possibly related to the treatment, and the dramatic increase of hemoglobin F, often in association with an increase of the total hemoglobin levels as a result of decreased hemolysis.

Acute Disease↗

PubMed1989

A phase I/II study of recombinant interferon alpha 2a and hydroxyurea for chronic myelocytic leukemia.

Nine previously untreated patients with Philadelphia chromosome-positive chronic myelocytic leukemia (CML) were treated with recombinant interferon alpha 2a (rIFN-alpha 2a) and hydroxyurea. Patients received 6 X 10(6) U rIFN-alpha 2a daily for the first week and 3 X 10(6) U rIFN-alpha 2a daily for the second week. As maintenance treatment starting on day 15, patients received 3 X 10(6) U rIFN-alpha 2a 3 times a week. Simultaneously, hydroxyurea was given, starting at a dose of 40 mg/kg on day one. The maintenance dosage was adjusted to the white blood cell count. Two patients responded with complete hematological remissions but without cytogenetic and molecular-genetic improvements. Seven patients responded with partial hematological remissions. Response to therapy was rapid; normal white blood cell counts were reached after a median of 12 days. The doses of rIFN-alpha 2a and hydroxyurea needed to keep the leucocyte count in the normal range were low (3 X 10(6) U rIFN-alpha 2a 3 times per week, 0.5-1.5 g hydroxyurea/day). Acute toxicity of the combination therapy consisted of fever (9 of 9 patients), flulike symptoms (7 of 9 patients), pruritus and/or rash (3 of 9 patients) and evidence of a tumor cell lysis syndrome (1 of 9 patients). The side effects were not dose-limiting. Combination therapy with rIFN-alpha 2a and hydroxyurea for CML is well tolerated and allows quick and effective hematological control of the disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1979

Isolation of hydroxyurea-resistant CHO cells with altered levels of ribonucleotide reductase.

A Chinese hamster ovary cell line selected for resistance to hydroxyurea was serially cultivated in the absence of a selective agent, and cells with decreased resistance to the cytotoxic effects of hydroxyurea gradually accumulated in the population. Three stable subclones with differing drug sensitivities were isolated from this mixed population and were found to contain intracellular levels of drug-sensitive ribonucleotide reductase which correlated with the degree of cellular resistance to hydroxyurea. This new class of hydroxyurea resistance was expressed in a codominant fashion in cell-cell hybridization studies. Also, the enhanced enzyme activity in the drug-resistant cells was observed only during the cell cycle S phase of synchronized cells. The properties of these drug-resistant lines indicate that they will be useful for genetic and biochemical studies.

Animals↗

PubMed1986

Characterization of a mouse cell line selected for hydroxyurea resistance by a stepwise procedure: drug-dependent overproduction of ribonucleotide reductase activity.

Hydroxyurea was used as a selective agent in culture, to isolate by a stepwise procedure, a unique mouse L cell line called LHF which exhibited a stable resistance to high concentrations of drug (5 mM). LHF cells contained an elevation in ribonucleotide reductase activity which depended upon whether cells were previously cultured in the presence or absence of hydroxyurea. M1 immunoprecipitation and M2 titration experiments indicated that both ribonucleotide reductase subunits were elevated in drug-resistant cells. Interestingly, a very large drug-dependent change in the M2 activity (about a 100-fold) was observed. Studies on enzyme activity with cycloheximide and actinomycin D indicated that the hydroxyurea-dependent increase in activity required de novo protein synthesis and transcriptional activity. These results are different from other ribonucleotide reductase overproducing cell lines previously described, and indicate that hydroxyurea modulates enzyme activity by an interesting mechanism.

Animals↗

PubMed2002

Treatment with hydroxyurea in thalassemia intermedia with paravertebral pseudotumors of extramedullary hematopoiesis.

Excessive ineffective erythropoiesis in thalassemia intermedia may cause paravertebral pseudotumors of extramedullary hematopoiesis. Due to the proximity to the spinal canal, these paravertebral masses carry the risk of severe neurological damage. Treatment strategies include hypertransfusion, radiotherapy, and laminectomy. Hydroxyurea, stimulating fetal hemoglobin synthesis, may represent an alternative therapeutic approach. We report on a 26-year-old patient suffering from thalassemia intermedia with progressive anemia symptoms and presenting multiple intrathoracic paravertebral pseudotumors of extramedullary hematopoiesis. Hypertransfusion therapy and splenectomy were followed by regular transfusion (baseline hemoglobin 10 g/dl) and chelation with desferrioxamine. With this treatment, clinical symptoms disappeared, paravertebral hematopoietic masses did not progress, but severe hemosiderosis developed within a few years. Hydroxyurea therapy was initiated to increase the efficacy of erythropoiesis, thereby reducing the required transfusion volume but suppressing concomitantly further expansion of extramedullary hematopoiesis, and finally leading to a reduction of transfusional iron load. Treatment was started with 4 mg/kg per day and stepwise increased to 12.5 mg/kg per day. The fetal hemoglobin concentration increased from 4.5 to 5.5 g/dl after 1 year and to 9.9 g/dl after 2 years of treatment. The yearly transfusion volume was halved during the 1st year of treatment. At present, after 26 months of treatment, the patient has been transfusion-independent for 10 months. Serum ferritin levels decreased from 2844 to 1335 ng/ml. Size and shape of paravertebral hematopoietic pseudotumors remained stable. No side effects of hydroxyurea have been observed. In thalassemia intermedia patients with extramedullary hematopoiesis, hydroxyurea may lead to independence from regular transfusion therapy without further expansion of ectopic hematopoietic tissue.

Adult↗

PubMed1999

Hydroxyurea-induced acute interstitial pneumonitis in a patient with essential thrombocythemia.

Hydroxyurea is a drug widely used to control myeloproliferative disorders, due in part to its relative lack of severe side effects. We present a case of acute interstitial pneumonitis in a patient who was treated with hydroxyurea for essential thrombocythemia. The clinical course suggests that the interstitial pneumonitis was induced by hydroxyurea. This is the first case of hydroxyurea-induced acute interstitial pneumonitis reported in the literature.

Humans↗

PubMed1976

Chain elongation and joining of DNA synthesized during hydroxyurea treatment of Chinese hamster cells.

We have previously presented evidence that hydroxyurea treatment of synchronized G1 Chinese hamster cells did not prevent the entry of cells into the DNA synthetic period but that the DNA synthesized during this period (in which total DNA synthesis was severely depressed) was quite small (Walters, R.A., Tobey, R.A. and Hildebrand, C.E. (1976) Biochem. Biophys. Res. Com. 69, 212-217). In view of the reported effects of hydroxyurea on deoxyribonucleoside metabolism and possible relationship to control of DNA replication (Bjursell, G. and Reichard, P. (1973) J. Biol. Chem. 248,3904-3909 and Walters, R.A., Tobey, R.A. and Ratliff, R.L. (1973) Biochim. Biophys. Acta 319, 336-347), we examined the fate of DNA synthesized during and shortly after hydroxyurea treatment to determine if this DNA exhibited any kinetic behavior which might be an indicator of aberrant synthesis. We found that, upon hydroxyurea removal, DNA grew at a linear rate of 0.98 +/- 0.12 - 10(6) dalton/min (0.98 +/- 0.12 mum/min) for about 2.3h. Beginning at 2.3 h, DNA with a molecular weight approx. 1.4 - 10(8) was very rapidly integrated into bulk DNA of greater than or equal to 3.5 - 10(8) daltons. The apparent growth rate of the 1.4 - 10(8) dalton DNA was approx. 10.6 mum/min. The data suggest that, at least for this DNA, joining into bulk DNA required one-third to one-half of the S period to begin and once begun, occurred very rapidly. The possibility of inegration of replicon clusters is considered.

Cell Division↗

PubMed1986

Evidence that the antitumor agent hydroxyurea enters mammalian cells by a diffusion mechanism.

Very little information is available about the process responsible for the uptake of the antitumor agent hydroxyurea by mammalian cells. Therefore we have investigated the transport of hydroxy[14C]-urea into Chinese hamster ovary cells. Using a convenient and reproducible 2 min. assay we found that hydroxyurea was taken up in a linear nonsaturable fashion between 0.01 mM and 100 mM drug. The Km for hydroxyurea uptake was essentially zero and the Vmax appeared to be infinite, suggesting a diffusion mechanism. The observation that intracellular drug concentrations were consistently less than medium concentrations indicated that uptake was not an active process. Experiments performed with the metabolic inhibitor sodium azide, and investigations at different assay temperatures also gave results consistent with a mechanism of drug diffusion. In total, the results obtained in this study are in agreement with the proposal that hydroxyurea enters the cell primarily by a process of diffusion. These observations provide a more complete understanding of the mode of action of this widely used drug.

Animals↗

PubMed1987

Reversion of hydroxyurea resistance, decline in ribonucleotide reductase activity, and loss of M2 gene amplification.

A key rate-limiting reaction in the synthesis of DNA is catalyzed by ribonucleotide reductase, the enzyme which reduces ribonucleotides to provide the deoxyribonucleotide precursors of DNA. The antitumor agent, hydroxyurea, is a specific inhibitor of this enzyme and has been used in the selection of drug resistant mammalian cell lines altered in ribonucleotide reductase activity. An unstable hydroxyurea resistant population of mammalian cells with elevated ribonucleotide reductase activity has been used to isolate three stable subclones with varying sensitivities to hydroxyurea cytotoxicity and levels of ribonucleotide reductase activities. These subclones have been analyzed at the molecular level with cDNA probes encoding the two nonidentical subunits of ribonucleotide reductase (M1 and M2). Although no significant differences in M1 mRNA levels or gene copy numbers were detected between the three cell lines, a strong correlation between cellular resistance, enzyme activity, M2 mRNA and M2 gene copies was observed. This is the first demonstration that reversion of hydroxyurea resistance is directly linked to a decrease in M2 mRNA levels and M2 gene copy number, and strongly supports the concept that M2 gene amplification is an important mechanism for achieving resistance to this antitumor agent through elevations in ribonucleotide reductase.

Animals↗

PubMed1976

Adaptation of the cells of Escherichia coli to the presence of hydroxyurea increases the level of inorganic pyrophosphatase acttivity.

Hydroxyurea, an inhibitor of ribonucleoside diphosphate reductase, completely arrested the net synthesis of DNA for 3-4 h, when it was added in 30 mM concentration to growing cultures of Escherichia coli K12. Thereafter the net synthesis of DNA started again, although slowly, and simultaneously with it the formation of inorganic pyrophosphatase activity was stimulated leading to a 2-fold increase in the specific activity of the enzyme in 2-3 h. Subsequently cell division began again. In this way a new steady state, stable in the presence of hydroxyurea, was reached. This new state was characterized by the high specific activity of inorganic pyrophosphatase, a small but constant amount of DNA/cell mass (1/4 of the normal value), and large elongated cells. All these changes were slowly reversed during 5-6 h, when the cells were transferred into a drug-free medium. The activity of isoleucyl-tRNA synthetase, assayed as a control, did not change significantly in the presence of hydroxyurea. Hydroxyurea had no effect on the activity of inorganic pyrophosphatase in vitro.

Chloramphenicol↗

PubMed1985

Effects of inhibiting DNA synthesis with hydroxyurea on stretch-induced skeletal muscle growth.

Growth of chicken patagialis muscle in response to passive stretch for 7 days was studied in the absence and presence of the DNA synthesis inhibitor hydroxyurea. In the absence of hydroxyurea, the DNA content and concentration of the stretched muscle increased 101% and 40%, respectively, relative to the unstretched contralateral control. Stretch-induced growth was characterized by large increases in muscle wet weight (56%), protein content (44%), RNA concentration (63%), cross-sectional area (67%), and mean fiber cross-sectional area (50%). In the presence of hydroxyurea, DNA content increased only 22% whereas DNA concentration decreased 11% in response to stretch. However, except for RNA concentration, which increased 84%, stretch-induced growth in the hydroxyurea-treated birds exhibited the same characteristics as those in the sham-treated animals. Therefore, the large increase in DNA content and concentration observed after 7 days of stretch-induced growth in the chicken patagialis muscle was not necessary for the growth to occur.

Animals↗

PubMed1976

The mutagenic activity of hydroxyurea in Chlamydomonas reinhardi.

Hydroxyurea, an inhibitor of ribonucleotide reductase, increases the frequency of streptomycin resistant mutants in liquid cultures of Chlamydomonas reinhardi after 45 h incubation. After more prolonged incubation in hydroxyurea medium the frequency of streptomycin resistant mutants declines. This may be due to the slower growth rate of streptomycin resistant mutants compared to wild type cells in hydroxyurea containing medium. Studies on solid medium show that both the rate of forward mutation to streptomycin resistance and reverse mutation to nicotinamide independence are increased several fold by growth on hydroxyurea.

Chlamydomonas↗

PubMed1979

Single-strand breaks in DNA during repair of UV-induced damage in normal human and xeroderma pigmentosum cells as determined by alkaline DNA unwinding and hydroxylapatite chromatography: effects of hydroxyurea, 5-fluorodeoxyuridine and 1-beta-D-arabinofuranosylcytosine on the kinetics of repair.

A simple and sensitive technique for detection of strand breaks in DNA has been further developed. The method has been used to follow UV-induced excision-repair in human fibroblasts. It has been possible to study the kinetics of enzymic reactions in intact cells, in which strand breaks in DNA are produced and sealed again. Hydroxyurea, 5-fluorodeoxyuridine and 1-beta-D-arabinofuranosylcytosine, potent inhibitors of DNA synthesis, drastically increased the number of breaks observed during the repair process. This was probably due to a decreased polymerase activity, which will cause the strand breaks formed by endonuclease to remain open longer. The initial rate of strand-break formation did not seem to be influenced by hydroxyurea or araC, and was about 4000 breaks per minute in a diploid genome, at a dose of 20 J/m2. After 5--30 min, depending on the dose of UV, the number of breaks reached a maximum and started to decrease again. Hydroxyurea decreased the rate of polymerization in the sites under repair. However, there was no concomitant reduction of repair-induced incorporation of [3H]thymidine and no reduction of the excision of pyrimidine dimers. It therefore seems that the action of the polymerase was not a rate-limiting event, but rather an earlier step. It is likely that the endonucleolytic activity determined the rate of repair. As a consequence, the endonuclease and polymerase cannot be bound in a permanent complex. Under certain assumptions, the time for repair of a site, i.e. the time from incision to final ligase sealing, can be estimated as between 3 and 10 min. Essentially no breaks were produced in Xeroderma pigmentosum cells belonging to complementation group A, and there was no enhancement by hydroxyurea. Cells from the variant type of Xeroderma pigmentosum behaved like normal cells in this respect.

Cell Line↗

PubMed1987

Effect of hydroxyurea on differentiation of mitotically inactive olfactory receptor cells in the frog.

Hydroxyurea is a widely used mitotic suppressant, but its action on nondividing cells remains largely unknown. This is a study of the effect of the drug on the development of newly generated, mitotically inactive olfactory receptor cells in adult frogs. To obtain olfactory epithelia consisting of newly generated cells, the original olfactory epithelia in a group of animals were ablated by irrigation of their nasal cavities with a solution of zinc sulfate in distilled water. The new epithelial cells were then allowed to generate over a period of 10 days. The hydroxyurea treatment was carried out by delivering a 50 mM concentration of the drug in Ringer's solution into the frogs' nasal cavities at a flow rate of 0.40 ml/day continuously for 24 days. Such treatment was capable of suppressing mitotic activity in olfactory epithelia. Morphological and electrophysiological observations of olfactory receptor cells, which were developing during hydroxyurea treatment, did not reveal any notable differences in comparison with olfactory receptor cells in control epithelia treated only with Ringer's solution. Thus the prolonged treatment of olfactory epithelia with hydroxyurea employed in this study, while suppressing mitotic activity in these tissues, did not significantly affect the differentiation of young postmitotic receptor cells.

Action Potentials↗

PubMed1987

Induction of the SOS response by hydroxyurea in Escherichia coli K12.

Hydroxyurea at concentrations higher than 10(-2) M induced the recA and sfiA genes of E. coli as well as the lambda prophage by a pathway independent of the recBC genes. In addition, the hydroxyurea-mediated induction of the SOS response is accompanied by a recA-dependent decrease on the cellular ATP pool. The presence of the multicopy plasmid pPS2, harboring the nrdAB genes (encoding the ribonucleoside reductase enzyme), abolished the hydroxyurea-induced expression of the recA gene. These data lead us to suggest that induction of the SOS response by hydroxyurea is due to the blocking of DNA replication by the inhibition of the ribonucleoside reductase complex activity.

Bacterial Proteins↗

PubMed1994

A phase II study of high-dose hydroxyurea and dacarbazine (DTIC) in the treatment of metastatic malignant melanoma.

Dacarbazine (DTIC) exerts its major biochemical effect through the formation of methylated DNA adducts. Hydroxyurea (HU) is a ribonucleotide reductase inhibitor which blocks DNA excision-repair by the depletion of intracellular ribonucleotides. Combination of HU and DTIC was used to enhance the activity of DTIC by inhibiting DNA repair. 16 patients with metastatic malignant melanoma were treated with the combination. All patients had measurable disease and none had received prior systemic therapy. Hydroxyurea was given as a continuous intravenous (i.v.) infusion of 1 g/h (total 36 g) and DTIC 1 g/m2 i.v. over 1 h, 23 h from the start of hydroxyurea infusion. 4 patients achieved partial remission with an objective remission rate of 25% [95% confidence interval (CI) 7-52%]. Median duration of response was 3.5 months. 3 of the responding patients had predominant visceral metastases. Disease was stabilised in 5 patients with a median time to progression of 16 months. The predominant toxicity to this treatment was gastrointestinal, with 3 patients developing grade 3 nausea/vomiting. Only 1 patient developed grade 3 leucopenia complicated by septicaemia. It is concluded that the combination of hydroxyurea and DTIC is a well-tolerated regimen with activity against visceral metastases from malignant melanoma but the duration of response to this treatment is short.

Adult↗

PubMed2004

Concomitant hydroxyurea plus radiotherapy versus radiotherapy for carcinoma of the uterine cervix: a systematic review.

We identified eight randomised control trials of hydroxyurea and radiation versus radiotherapy alone (six published in full and two abstracts). Most concluded that outcomes were improved by use of hydroxyurea. However, methodological problems associated with these trials included small sample size, a large number of patient exclusions post randomisation, differing outcome definitions, subgroup analyses of already small numbers of patients and questionable rules for censoring, particularly a failure to include treatment related deaths in the survival analysis. All but two studies were of less than 50 patients. Patients were excluded from some analyses for treatment related reasons. The exclusion of such patients undoubtedly altered the conclusions of the studies. Even if there was a survival advantage attributed to hydroxyurea, overall survival was somewhat poor. We found the evidence regarding the use of hydroxyurea and radiotherapy to be inadequate for assessing its role in the treatment of cervical cancer.

Antineoplastic Agents↗

PubMed2003

Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest.

Severe levels of hypoxia (oxygen concentrations of less that 0.02%) have been shown to induce a rapid S-phase arrest. The mechanism behind hypoxia-induced S-phase arrest is unclear, we show here that it was not mediated by a shortage of nucleosides and was not dependent on p53, p21 or Hif 1alpha status. The drugs aphidicolin and hydroxyurea both induce rapid replication arrest and have been used throughout the literature to study the ATR-mediated response to stalled replication. We have shown previously that hypoxia induces ATR-dependent phosphorylation of p53, Chk1 and histone H2AX. Using comet-assays to detect DNA-damage we found that both aphidicolin and hydroxyurea induced significant levels of DNA-damage while hypoxia did not. Here we show that like aphidicolin and hydroxyurea, hypoxia induces phosphorylation of Nbs1 at serine 343 and Rad17 serine 645. Hypoxia-dependent phosphorylation of Nbs1 and Rad17 was ATM-independent and therefore likely to be a result of the ATR kinase activity. In contrast, p53 was phosphorylated differentially in response to the three treatments considered here. p53 was phosphorylated at serine 15 in response to all three treatments but was only phosphorylated at serine 20 in response to the drug treatments. We propose that treatment with either aphidicolin or hydroxyurea leads to not only replication arrest but also DNA-damage and therefore both ATM and ATR-mediated signaling. In contrast replication arrest induced by severe hypoxia is sensed exclusively through ATR, with ATM only having a role to play after re-oxygenation.

Animals↗