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PubMed1987

The effect of hydroxyurea on the expression of the common fragile site at 3p14.

Hydroxyurea (HU) is an inhibitor of DNA synthesis, which can inhibit the enzyme ribonucleotide reductase, reduce the syntheses of all four deoxyribonucleoside diphosphates (dNDP), and disturb the balance of the dNTP pool. We have studied the effect of HU on the common fragile site at 3p14 (FRA3B) and have found that G2 treatment with HU increased not only the frequency of chromosomal aberration but also the expression of FRA3B in both complete and folate deficient media. There is a synergistic effect between HU and growth in folate deficient medium on the induction of FRA3B. Our results suggest that the inhibition of DNA repair, including the inhibition in G2 phase, plays an important role in the expression of FRA3B, supporting other authors' data on the effect of other DNA repair inhibitors, such as aphidicolin, caffeine, 1-beta-D-arabinofuranosylcytosine, and 5-fluorodeoxyuridine, on the expression of FRA3B.

Caffeine↗

PubMed1992

Multisystemic eosinophilic epitheliotropic disease in a horse: attempted treatment with hydroxyurea and dexamethasone.

Equine multisystemic eosinophilic epitheliotropic disease is rare in horses. The clinical signs vary according to the organs affected, the skin and gastrointestinal tract being most commonly involved. This paper gives the first reported description of a horse with multisystemic eosinophilic epitheliotropic disease in the United Kingdom and the attempts to treat it. The horse showed dermatological, gastrointestinal, hepatic, pulmonary and pancreatic involvement. Some improvement was seen when the horse was treated with corticosteroid and hydroxyurea.

Animals↗

PubMed1980

The effect of hydroxyurea on meiosis and genetic recombination in the fungus Coprinus lagopus.

Treatment with hydroxyurea (HU) inhibits fruitbody development in Coprinus lagopus (sensu Lewis). The two most sensitive meiotic stages are mid-late premeiotic S phase and the pachytene-diplotene period. A 2 or 4 h treatment at mid-late premeiotic S phase arrests fruitbody development. If the same treatment is given at pachytene and diplotene, the fruitbody completes meiosis but the spores produced are inviable. The spores from fruitbodies treated at pachytene appear to be normal whereas those treated at diplotene are empty because the four nuclei remain in the basidium. A 2 or 4 h treatment with HU during karyogamy causes a decrease in spore viability and a dramatic increase in recombination frequency. The same treatment at metaphase II or later stages causes little damage to fruitbody development or spore viability. The effects of HU on the meiotic cell cycle suggest that the drug exerts its effect by inhibiting the synthesis of deoxynucleotides.

Agaricales↗

PubMed1985

Spermatogenic delay and increased chiasma frequency in T70H/+ male mice with hydroxyurea-Trenimon limited spermatocyte populations.

T(1;13)70H/+ male mice were treated with hydroxyurea (HU) and Trenimon (T). This karyotype offers excellent possibilities for estimating number and position of chiasmata and segregation in meiotic anaphase I. By their cell-killing action during spermatogenesis, HU and T produce large gaps in the spermatogenic line. The surviving population between the gaps was analysed at diakinesis--metaphase I and metaphase II. We found by autoradiography a considerable retardation of the development from resting primary spermatocytes (RPS) to metaphase I and II as compared to untreated T70H/+ males. Furthermore we found increased chiasma frequencies in diakinesis--metaphase I (MI) and reduced nondisjunction frequencies at anaphse I as a result of the treatments applied. The latter effect could not be explained by the increased chiasma frequency.

Animals↗

PubMed1998

Cytokines and soluble adhesion molecules in sickle cell anemia patients during hydroxyurea therapy.

Hydroxyurea (HU) induces HbF production and can reduce painful crises in some patients with sickle cell anemia (SS). However, HbF induction alone cannot explain the beneficial effect of HU treatment as some patients experience clinical improvement while showing only minor increases in HbF. Other actions of HU, in particular its effects on vascular endothelium, adhesion molecule expression and cytokine production may also play a role in the final therapeutic outcome. In order to analyze these effects we studied the levels of interleukin-3 (IL-3), interleukin-6, granulocyte-macrophage colony-stimulating factor, erythropoietin, stem cell factor, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1, soluble E-selectin and soluble P-selectin in 7 SS patients before and during 5 months of HU treatment. Use of HU seems to have no detectable effect on soluble adhesion molecules, but the steady state levels of soluble vascular adhesion molecule-1 are enhanced in SS patients compared to normal controls. Of the cytokines studied, only IL-3 showed an increase during therapy, suggesting HU may induce early erythroid progenitors capable of producing HbF by a direct or indirect effect on IL-3 production. Remarkably, the steady state stem cell factor levels in sickle cell patients seemed to be decreased compared to healthy controls.

Adult↗

PubMed1999

Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy.

It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-alpha, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

Adolescent↗

PubMedDate not supplied

Pharmacokinetic profile of the anti-sickling hydroxyurea in wild-type and transgenic sickle cell mice.

The pharmacokinetic profile of hydroxyurea (HU) was investigated by measuring the rate of drug disappearance from the plasma in wild-type and transgenic (Tg) sickle cell mice. The absorption and elimination processes of HU exhibited first-order kinetics after intraperitoneal administration of HU at 10, 50, 100 or 200 mg/kg body weight (BW). The dosage had a marked effect on the pharmacokinetics of HU in the Tg sickle cell mice. Although the area under the plasma concentration curve (AUC) increased in direct proportion with the HU dose in the wild-type mice, the AUC increased to a much greater extent at higher doses in the Tg sickle cell mice. In the Tg sickle cell mice, there was a considerable increase in the mean residence time (MRT) and a significant reduction in the apparent clearance (CL/F) at HU dose > or =100 mg/kg BW, when compared to the lower doses. At an HU dose of 200 mg/kg BW, the CL/F in the Tg sickle cell mice was reduced by about 50% of the value obtained at a dose of 10 mg/kg BW. This phenomenon was not noticeable in the wild-type mice. The MRT value in the wild-type mice at all doses was relatively constant. The steady-state distribution volume of HU in both the wild-type and Tg sickle cell mice was relatively constant at all doses of the drug. The AUC, CL/F, MRT, and terminal half-life values at any given HU dose showed significant differences between the wild-type and Tg sickle cell mice. Following intraperitoneal administration of HU at a dose of 10, 50, 100, or 200 mg/kg BW, the mean percentage of HU excreted in the urine of the wild-type and Tg sickle cell mice over 120 min was 84 +/- 6.4% and 50 +/- 8.2%, respectively, indicating a significant difference in the amount of HU excreted in urine in the two kinds of mice. The results obtained in this study may be useful in establishing an optimal dose of HU in the treatment and management of patients with sickle cell disease and other hemoglobinopathies.

Anemia, Sickle Cell↗

PubMed1978

Replication of equine herpesvirus type 1 and type 3: resistance to hydroxyurea and thymidine.

The replication of equine herpesvirus type 1 (EHV-1) and type 3 (EHV-3) was unimpeded in three different cell types-equine epithelial cells, equine fibroblasts, and mouse fibroblasts-which had been blocked in their capacity to synthesize host DNA by 2.5 mM hydroxyurea (HU) or 2 mM thymidine (TdR). The rate of DNA synthesis in uninfected or equine herpesvirus-infected cells in the presence of HU or TdR was measured by pulse-labeling cell samples with a labeled DNA precursor at different times after infection. DNA synthesis in uninfected cultures was completely inhibited by both compounds. However, in cells infected with EHV-1 or EHV-3 and incubated in the presence of HU or TdR, a burst of DNA synthesis occurred which coincided in time with that of virus-specific DNA replication in infected cells without inhibitors. Analysis by cesium chloride isopycnic centrifugation confirmed that the DNA made in drug-treated, infected cells was viral. A possible mechanism of the HU and TdR resistance of the equine herpesviruses is the induction of a ribonucleotide reductase which is insensitive to inhibition by these compounds.

Animals↗

PubMed1997

Hydroxyurea therapy in sickle cell anemia patients in Curaçao, The Netherlands Antilles.

We have treated 9 patients with sickle cell anemia (SS) with hydroxyurea (HU). All 9 patients carried 4 alpha-globin genes and the beta s-globin haplotypes 19/19 (Benin/Benin), except for 1 who had haplotype 19 together with type 3 (Benin/Senegal). Six patients received HU for 10 months and were again treated with the drug for 5 months after an interval of 1 year. One patient was given HU for 22 consecutive months. A record was kept of hematological and biochemical data, Hb F and G gamma levels, as well as possible clinical complications. Our data show that HU generally improves the hematological and biochemical values and the level of Hb F, and reduces painful crises in some patients. However, although the clinical symptoms improved in some patients during HU therapy, the older patients did not observe any changes in their general condition; the same is the case for the patient with haplotype 19/3. One patient also experienced life-threatening liver sequestration during treatment. We conclude that the selection of patients who may benefit from HU therapy needs further evaluation.

Adult↗

PubMed1997

Lymphoid blast crisis during complete cytogenetic remission following interferon-alpha and hydroxyurea therapy.

Chronic myelogenous leukemia (CML) is a clonal disorder starting with a chronic phase and progressing to an acute blastic phase. Philadelphia (Ph) chromosome formation results in the relocation of the ABL oncogene from the chromosome 9q34 to BCR region on 22q11, forming the BCR/ABL fusion gene. The Ph chromosome once detected rarely disappears, except as a result of therapy. We present an unusual Ph-positive CML case, which developed lymphoid blast crisis in complete cytogenetic remission following interferon-alpha and hydroxyurea therapy. Sequential cytogenetic investigations were carried out on bone marrow. After a standard Ph translocation seen at diagnosis, from the 8th month of therapy all metaphases showed a normal diploid karyotype. Fluorescence in situ hybridization detected residual BCR/ABL-positive interphase cells during the 12th month of therapy. In the 14th month, the patient showed 27% blasts in marrow though normal cytogenetics was maintained. Present findings suggest blastic transformation occurred in a Ph-negative lymphoid clone. This supports the hypothesis that an actual leukemogenic event occurs in a multipotent stem cell prior to the acquisition of Ph translocation.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Combination therapy with interferon alfa-2b and hydroxyurea during the accelerated phase of chronic myelogenous leukemia.

Inferferon alfa-2b (IFN) plays a major role in the current management of previously untreated patients with chronic myelogenous leukemia (CML) as well as patients with CML who have relapsed after bone marrow transplantation. Hydroxyurea (HU) is the best conventional drug for treatment of CML in the chronic phase. Ten patients, six men and four women, 40-70 years of age, were treated during the accelerated phase of CML with a combination of IFN and HU. Patients had received only HU during the chronic phase of the disease. All patients were positive for the Philadelphia chromosome and had an excess number of blasts in peripheral blood smears (more than 10%), as well as increased numbers of basophils and eosinophils but a low leukocyte level of alkaline phosphatase. Eight of them had splenomegaly. Five patients (50%) survived for 1-3 years, achieving complete hematological remission. Three patients had a partial hematological response and died within 1-2 years. Two patients with aggressive disease died within 3 months of the blastic crisis. It appears that combination therapy with IFN and HU might be a useful alternative for patients in the accelerated phase of CML who have failed to respond to HU alone.

Adult↗

PubMed1995

The pharmacological manipulation of fetal haemoglobin: trials using hydroxyurea and recombinant human erythropoietin.

Hydroxyurea (HU) and recombinant human erythropoietin (rHuEpo) have been used in several studies to elevate Hb F level in sickle cell disease (SCD) patients and hence to ameliorate the clinical presentations of the disease. The treatment protocol and doses have varied in the different studies. We studied the effects of HU+rHuEpo combination therapy in sickle cell anaemia (SCA patients) to investigate the Hb F manipulation and hence treatment of SCA. Six patients with severe SCA were selected for treatment with HU (20-25 mg/kg body weight) and rHuEpo (400-800 U/kg body weight) combination therapy for 4 weeks followed by HU (20-25 mg/kg body weight) maintenance therapy for 6 months to 1 year. Iron and folic acid were administered during HU+rHuEpo treatment. Signs, symptoms and complications were recorded to obtain the severity index. Only patients with a severity index > or = 6 were included in the study. Haematological and biochemical parameter values, Hb A2, Hb F, Hb F distribution, Hb F cells, bilirubin level and reticulocyte count were assessed at least on 2-3 occasions prior to initiation of the therapy protocol to establish baseline values. During the treatment period, the clinical presentations were monitored and the estimation of the laboratory parameters was carried out every 4-8 weeks. The results of these parameters during HU and rHuEpo combination therapy and HU maintenance therapy were compared with baseline values using paired t test. The elevation in the level of Hb F, Hb F cells, total haemoglobin, red cell count and MCV were significant (p < 0.005), while reticulocyte count and total bilirubin were significantly decreased (p < 0.05). Each patient showed an individual pattern of Hb F elevation. The increase in Hb F level was correlated with the haematological and biochemical parameters using the General Linear Model Programme of Statistical Analysis System. In general, the clinical presentation improved as Hb F level increased in each patient. In addition, the positive correlation with the haematological parameters and negative correlation with reticulocytes and total bilirubin confirmed the beneficial effect of elevated Hb F level on reducing red cell haemolysis. No correlation could be demonstrated between the pretreatment Hb F level and the increase in Hb F during the treatment period. Daily doses of HU with a single intravenous rHuEpo and iron supplementation elevate Hb F and Hb F cells in SCA patients. The Hb F level can be maintained high on HU therapy alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1992

Hydroxyurea for the treatment of sickle cell disease.

In this study 21 adults with severe form of sickle cell disease (SCD; sickle cell anaemia, n = 15; Hb S/beta degree-thal, n = 6) were treated with hydroxyurea (HU) to assess the effectiveness of the drug in managing SCD. The individual dose was selected for each patient. The dose selection was based on the HU clearance study. Thereafter, the patients received daily doses of 15-20 mg/kg body weight. An evaluation data form was filled out at the monthly visit. The severity index (SI) of the disease was determined and haematological parameters including red cell indices, platelet counts, reticulocyte counts, irreversibly sickled cells, red cell deformability, Hb F, Hb F cells, total and direct bilirubin levels were measured prior to treatment, at follow-up intervals during treatment and after cessation of treatment. The trial period lasted 3 months. Statistically significant improvement was observed in the clinical presentation, haematological and biochemical parameters. Hb F level and F cells showed a significant increase in most patients, but to a variable degree. A major resultant effect was an increase in mean cell volume. Our experience shows that HU can be used for the treatment of severe forms of SCD with no major side effects, provided that the doses are monitored and that laboratory investigations are regularly undertaken.

Administration, Oral↗

PubMed1987

High-voltage irradiation and hydroxyurea for pulmonary leukostasis in acute myelomonocytic leukemia.

A 29-year-old man with acute myelomonocytic leukemia had an initial leukocyte count of 192 X 10(9) cells/l and 84% blasts. During the initial treatment with hydroxyurea, 1 g/m2 orally tid, he developed pulmonary leukostasis which responded rapidly to whole-lung radiation with 1.5 Gy in one fraction. Pulmonary leukostasis in hyperleukocytotic AML is an oncologic emergency demanding rapid intervention. The combined treatment with chemotherapy and radiation appears useful.

Adult↗

PubMed1977

Influence of cytostatics on some platelet functions in vitro. V. Hydroxyurea.

Hydroxyurea added to citrated platelet-rich plasma in vitro did not influence the aggregation of the platelets, their adhesion to glass, their release of aggregating activity, platelet factor 4 or availability of platelet factor 3. Neither did it have any effect on the uptake of 14C-serotonin, the reptilase clot retraction or the coagulation system.

Blood Platelets↗

PubMed1977

Alteration of rat bone marrow megakaryocytes following administration of cytosine arabinoside, daunomycin and hydroxyurea.

The in vivo effects of three cytotoxic agents--cytosine arabinoside, daunomycin and hydroxyurea on rat bone marrow megakaryocytes were studied, specifically the relative count, the type percentage and the morphology. All three agents caused thrombo-cytopenia, a decrease in the number of megakaryocytes relative to the nucleated bone marrow cells, and a decrease in the percentage of megakaryoblasts, associated with an increase in the percentage of granular megakaryocytes. A decreased lobulation of the megakaryocytes was observed following the administration of cytosine arabinoside and of daunomycin. Thrombosthenin, examined immunologically, remained detectable in the bone marrow smears throughout the various stages of megakaryocyte alteration.

Animals↗

PubMed1975

Combined 5-fluorouracil and hydroxyurea therapy for gastrointestinal cancer.

19 patients with metastatic gastrointestinal malignancy were treated with a regimen of 5-fluorouracil (FU) 500 mg/m2 intravenously and hydroxyurea (HU) 80 MG/KG orally administered on consecutive days weekly. Antitumor responses were not observed and an unusually high incidence of neurotoxicity (21%) was noted related to dose. It is suggested that the lack of therapeutic effect and the observed toxicity may be related to the biochemical interaction of FU and HU resulting in an inability to convert FU to the active metabolite and an accumulation of catabolic products with neurotoxic effects.

Administration, Oral↗

PubMed1983

Induction of differences in the circadian profiles of DNA synthesis between normal and neoplastic cell populations by hydroxyurea without perturbation of the normal circadian rhythms.

This paper presents data which support a previously stated hypothesis that differences in phasing can be induced in the rhythms of DNA synthetic activity (DNA-SA) between normal and neoplastic cell populations in the same animal. The drug used was hydroxyurea (HU). Mice were standardized to a light-dark cycle with light from 06.00 to 18.00 h. Minimal disruption of the normal circadian pattern in DNA-SA in tongue, esophagus, and rectum occurred when 500 mg/kg HU was given at 17.00 h. The same dose of HU given at 05.00 h resulted in significant perturbation of the normal circadian pattern of DNA-SA in these organs. 500 mg/kg HU at 17.00 h did, however, significantly perturb DNA-SA in the Ehrlich's ascites cardinoma (EAC). To study this phenomenon further the following experiments were done in EAC bearing mice: (A) 500 mg/kg HU given at 09.00, 13.00 and 17.00 h; (B) 500 mg/kg HU given at 21.00, 01.00 and 05.00 h, and (C) 3,000 mg/kg given at 17.00 h. In general, the response of the normal organs to HU varied depending on the circadian time of treatment with HU, whereas the response of the EAC was more uniform regardless of when the HU was given. By plotting the data obtained from the 3 normal organs and the EAC on the same graph specific points could be identified when: (a) maximal DNA-SA occurred in the EAC and at the same time minimal DNA-SA occurred in tongue, esophagus, and rectum, or (b) various levels of DNA-SA occurred in the EAC, but, at the same time maximal or peak levels of DNA-SA occurred in the normal organs.

Animals↗