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PubMed1980

Increased activation of 1-beta-D-arabinofuranosylcytosine by hydroxyurea in L1210 cells.

Hydroxyurea (0.1 to 10 mM), incubated with L1210 cells in the presence of 1 microM 1-beta-D-arabinofuranosylcytosine (ara-C), produced a concentration- and time-dependent increase in levels of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). This effect was abolished upon removal of hydroxyurea from cells. The enhancement of ara-CTP by hydroxyurea was observed for concentrations of ara-C ranging from 0.1 to 100 microM. These changes were not associated with alteration in the activity of deoxycytidine kinase, measured in extracts from L1210 cells both with and without deoxycytidine triphosphate. Hydroxyurea did, however, increase the apparent maximum velocity of this enzyme when determined with intact cell preparations, a finding consistent with alteration in endogenous regulation of this enzyme. Four-hr i.v. infusion of hydroxyurea (192 mg/kg/hr) with ara-C (1 mg/kg/hr) into ascites tumor-bearing mice also resulted in increased L1210 cell concentrations of ara-CTP. ara-C levels in plasma and L1210 cells were unaffected by hydroxyurea. Therefore, the enhancement of ara-CTP concentration in vivo, like in vitro, resulted from changes in ara-C conversion in the L1210 cells.

Animals↗

PubMed1995

[Multiple keratosis induced by hydroxyurea].

INTRODUCTION: Specific skin manifestations including skin atrophy and stripes of erythema on the extremities have been reported in patients with long-term treatment with hydroxyurea (HU). CASE REPORT: A 60-year-old patient who had been treated with HU since 1986 for chronic myeloid leukaemia presented in March 1992 with lesions characteristic of HU-induced skin changes. Hydroxyurea was continued for two more years and the lesions worsened. Unusually encountered multiple skin keratoses developed rapidly creating a clinical picture compatible with carcinomatous transformation until the withdrawal of hydroxyurea. DISCUSSION: The chronology and the clinical signs were in favour of implicating hydroxyurea in the development of these keratoses. The literature on the subject revealed one comparable case with actinic keratoses and multiple skin carcinomas. The interactions between hydroxyurea and the keratinocytes of the basal layer could explain different aspects of hydroxyurea-related toxidermia. The most severe manifestation could be the development of epithelial skin cancer.

Female↗

PubMed1996

A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy.

During 24 weeks of hydroxyurea treatment, we monitored red blood cell (RBC) parameters in three patients with sickle cell disease, including F-cell and F-reticulocyte profiles, distributions of delay times for intracellular polymerization, sickle erythrocyte adherence to human umbilical vein endothelial cells in a laminar flow chamber, RBC phthalate density profiles, mean corpuscular hemoglobin concentration and cation content, reticulocyte mean corpuscular hemoglobin concentration, 1H-nuclear magnetic resonance transverse relaxation rates of packed RBCs, and plasma membrane lateral and rotational mobilities of band 3 and glycophorins. Hydroxyurea increases the fraction of cells with sufficiently long delay times to escape the microcirculation before polymerization begins. Furthermore, high pretreatment adherence to human umbilical vein endothelial cells of sickle RBCs decreased to normal after only 2 weeks of hydroxyurea treatment, preceding the increase in fetal hemoglobin levels. The lower adhesion of sickle RBCs to endothelium would facilitate escape from the microcirculation before polymerization begins. Hydroxyurea shifted several biochemical and biophysical parameters of sickle erythrocytes toward values observed with hemoglobin SC disease, suggesting that hydroxyurea moderates sickle cell disease toward the milder, but still clinically significant, hemoglobin SC disease. The 50% reduction in sickle crises documented in the Multicenter Study of Hydroxyurea in Sickle Cell Disease is consistent with this degree of erythrocyte improvement.

Adult↗

PubMed1998

Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. The German CML Study Group.

Hydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyurea or interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of the German CML Study Group. Survivals were compared using proportional hazards regression with fixed and time-dependent variables to adjust for patient differences and changing risks over time. For the first 18 months after diagnosis, mortality was higher in the transplant than the nontransplant cohort (relative risk [RR], 5.85; P < .0001). From 18 to 56 months, mortality was similar (RR, 0.80; P = .38). After 56 months, mortality was lower in the transplant cohort (RR, 0.16; P < .0001). Seven-year survival probabilities (95% confidence interval) were 58% (50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for transplants starting 5.5 years after diagnosis. For transplants done within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study confirms higher early mortality, but a long-term survival advantage for HLA-identical sibling transplants over hydroxyurea or interferon in CML.

Adolescent↗

PubMed1998

Differential regulation of A gamma and G gamma fetal hemoglobin mRNA levels by hydroxyurea and butyrate.

In clinical studies, both hydroxyurea and butyrate increase fetal hemoglobin expression and ameliorate the symptoms of sickle cell anemia. However, comparative studies of the effects of hydroxyurea and butyrate on the expression of the individual fetal hemoglobin genes, A gamma and G gamma, have not been performed. The present study reports the effects of hydroxyurea and butyrate on steady-state A gamma and G gamma mRNA levels in K562 cells. Because the high degree of homology between the A gamma and G gamma cDNA sequences precludes the use of large cDNA probes for detection of individual fetal hemoglobin gene products, we investigated the specificity of two 20-base oligonucleotide probes synthesized from the region of greatest sequence diversity between these genes. Hybridization experiments demonstrated that the A gamma oligonucleotide probe was specific for A gamma DNA and RNA sequences and the G gamma oligonucleotide probe was specific for G gamma DNA and RNA sequences. These oligonucleotide probes detected both A gamma and G gamma mRNAs in K562 cells. In K562 cells treated with 2 mM sodium butyrate for 168 hours, the G gamma mRNA level increased 3.6-fold, whereas the A gamma mRNA level was not significantly different from untreated cells. Similar results were obtained when K562 cells were treated with 80 microM hydroxyurea. The G gamma mRNA level increased 2.3-fold at 168 hours, whereas the A gamma mRNA level did not change. The above results demonstrate that both butyrate and hydroxyurea selectively increase G gamma expression. Selective regulation of individual fetal hemoglobin genes is also seen in human development, where approximately 70% of the total fetal hemoglobin in the fetus is G gamma. Therefore, understanding the mechanisms by which butyrate and hydroxyurea differentially regulate fetal hemoglobin gene expression may provide insights into the developmental regulation of hemoglobin expression as well as the mechanisms of action of pharmacological agents currently being used to treat sickle cell disease.

Butyrates↗

PubMed1995

[Hydroxyurea, erythrocyte volumes and hemoglobin F].

Hydroxyurea is used in the treatment of sickle cell anemia and beta-thalassemia major to increase the content of hemoglobin F (HbF) and presumably ameliorate clinical symptoms. Under therapy with hydroxyurea an increase of the mean corpuscular volume (MCV) of the erythrocytes can be observed. To evaluate a possible estimation of the content of HbF using the increase of MCV under treatment with hydroxyurea, we measured MCV and HbF during therapy with hydroxyurea. The median MCV before therapy was 87.8 fl (range 74.3-95.7) and under hydroxyurea 104.1 fl (81.0-139.5), and the median HbF 1.8% (0.1-5.4). Although both MCV and HbF increased under treatment with hydroxyurea, a linear correlation between these two parameters was not detectable. Therefore, MCV cannot replace the measurement of HbF.

Erythrocyte Indices↗

PubMed2001

Hydroxyurea for sickle cell disease.

BACKGROUND: Sickle cell disease is one of the most common inherited diseases world wide. It is associated with life long morbidity and a reduced life expectancy. Hydroxyurea, a chemotherapeutic drug taken by mouth, raises fetal haemoglobin and, as such, is expected to ameliorate some of the clinical problems of sickle cell disease. OBJECTIVES: To assess the effects of hydroxyurea therapy in sickle cell disease patients of all types, of any age, regardless of setting. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialised register of controlled trials for haemoglobinopathies, which comprises references identified from comprehensive electronic database searches, hand-searching relevant journals, and hand-searching abstract books of conference proceedings. Date of the most recent search(es): November 2000. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing the use of oral hydroxyurea for one month or longer with placebo, standard therapy or other interventions for the treatment of patients with sickle cell disease. DATA COLLECTION AND ANALYSIS: Both reviewers independently assessed trial quality and extracted data from the two studies included. MAIN RESULTS: Twenty trials were found of which two trials, which reported results from a total of 324 adults and children were suitable for inclusion in the review. From the data provided in the published reports only one study (the MSH study to the United States of America) could be analysed. This study showed marked differences in favour of hydroxyurea treatment as compared with placebo in terms of annual crisis rate, use of transfusions, and life-threatening complications (in particular, the acute sickle chest syndrome). No serious adverse effects were reported from either study. REVIEWER'S CONCLUSIONS: While hydroxyurea appears both effective and safe in the severely affected SS adults over a two year period; further studies are required to elucidate its role in other patient groups and for other conditions.

Antisickling Agents↗

PubMed2003

Hydroxyurea-induced splenic regrowth in an adult patient with severe hemoglobin SC disease.

Hydroxyurea has been extensively used in patients with sickle cell anemia and severe sickle cell-hemoglobin C (SC) disease to reduce the severity of their diseases. We report here our experience with an adult patient with severe SC disease who developed symptomatic splenomegaly requiring splenectomy while being treated with hydroxyurea. This case suggests that hydroxyurea might restore some splenic function in functionally asplenic patients with sickle cell anemia or SC disease, but also raises the clinical concern that hydroxyurea may induce splenic regrowth, resulting in symptomatic splenomegaly. With the increasing use of hydroxyurea in the management of SS disease or other hemoglobinopathies, the importance of spleen monitoring must be further emphasized in these patients.

Adult↗

PubMed2005

Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.

Blotting, Western↗

PubMedDate not supplied

Increased ribonucleotide reductase activity in hydroxyurea-resistant mosquito cells.

Hydroxyurea-resistant Aedes albopictus mosquito cells were selected by incremental exposure of unmutagenized cells to hydroxyurea concentrations ranging from 0.1 to 8 mM. Clonal populations that had become 40-fold more resistant to hydroxyurea than wild-type cells varied in morphology, and their growth rate decreased to a;45 h doubling time, relative to an 18 h doubling time in unselected cells. At this level of resistance, the cells remained diploid, with a modal chromosome number of 6. When labelled with (35)S[methionine/cysteine], clone HU1062, which grew in the presence of 8 mM hydroxyurea, overproduced a labeled protein with the approximate size of the 45,000 dalton M2 subunit of ribonucleotide reductase. Consistent with this observation, ribonucleotide reductase activity in HU-1062 cells was approximately 10-fold higher than in wild-type control cells. This is the first example of an hydroxyurea-resistant insect cell line. [Originally published in Volume 34, Archives of Insect Biochemistry and Physiology, 34:31-41 (1997).]

Aedes↗

PubMed1988

Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha.

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

Busulfan↗

PubMed1993

Effects of hydroxyurea and cyclic adenosine monophosphate/protein kinase A inhibitors on the expression of the human chorionic gonadotropin alpha subunit and c-myc genes in choriocarcinoma.

We have previously shown that treatment of choriocarcinoma cells with methotrexate or hydroxyurea leads to both cessation of cell growth, accompanied by repression of c-myc oncogene expression, and induction of genes associated with the placental phenotype, including both subunits of human chorionic gonadotropin (hCG) and placental alkaline phosphatase. Since the genes induced by these antimetabolites are also cyclic AMP inducible, we hypothesized that these antimetabolites may cause activation of the cyclic AMP/protein kinase A pathway, suppressing genes associated with cellular proliferation and inducing placental gene expression. Three inhibitors of the cyclic AMP/protein kinase A pathway were assayed for their ability to inhibit the induction of the human chorionic gonadotropin alpha gene by hydroxyurea, and none of these inhibitors eliminated this induction. In addition, blockade of the cyclic AMP/protein kinase A pathway did not reverse the suppression of c-myc by hydroxyurea. The results of the inhibitor studies suggest that hydroxyurea acts independently of the protein kinase A pathway to stimulate gene expression, and that suppression of c-myc is insufficient to cause the induction of the human chorionic gonadotropin alpha gene by hydroxyurea.

Choriocarcinoma↗

PubMed2002

Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium Trial.

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.

Adult↗

PubMed1981

Effects of hydroxyurea on hemodynamics of pregnant rabbits: a maternally mediated mechanism of embryotoxicity.

Hydroxyurea is a cytotoxic agent used in the management of chronic granulocytic leukemia. This compound is teratogenic and embryolethal in various animal species, and has been widely used in experimental studies aimed at understanding the possible mechanisms of drug-induced malformations. Previous studies from our laboratory have demonstrated that maternal subcutaneous injections of hydroxyurea produce immediate circulatory alterations in rabbit embryos similar to those observed subsequent to uterine artery occlusion. The present study was designed to investigate the possibility that the embryolethal and teratogenic properties of hydroxyurea might be due to alterations in maternal hemodynamics, i.e., constriction of the uterine vasculature, resulting in exposure of the embryo to uterine ischemia at critical stage of in utero development. This study demonstrates that hydroxyurea significantly alters blood pressure and heart rate and produces significant uterine vasoconstriction. The resulting reductions in uterine blood flow (77%) elicited by hydroxyurea may be associated with its immediate embryotoxicity.

Abnormalities, Drug-Induced↗

PubMed1985

Survival of nonsurgically staged patients with negative lymphangiograms who had Stage IIB carcinoma of the cervix treated by pelvic radiation plus hydroxyurea.

Twenty patients with Stage IIB carcinoma of the cervix who did not undergo pretherapy para-aortic lymphadenectomy, but who had negative preradiation therapy lymphangiograms, were treated with pelvic radiation plus hydroxyurea. Patients received a median of 5020 rads of pelvic radiation plus 4000 rads of radium to point A. During radiation therapy and for a total of 12 weeks, patients received hydroxyurea administered at a dose of 80 mg/kg of body weight every 3 days if the white blood cell count was greater than or equal to 2,500/mm3 and platelets were greater than or equal to 75,000/mm3. The median follow-up time was 28 months (6 to 83 months). The estimated 5-year survival rate was 92%. Seventeen patients are alive with no evidence of disease (median, 28 months); one died of intercurrent disease with no evidence of disease (17 months); one is alive with no evidence of disease after recurrence (18 months); and one died of cervical cancer (22 months). The survival rate of patients with nonsurgically staged negative pretherapy lymphangiograms who had Stage IIB cervical cancer treated by pelvic radiation therapy plus hydroxyurea approximated the improved survival rate reported for patients with negative pretherapy para-aortic lymphadenectomy who were treated with pelvic radiation therapy plus hydroxyurea. Both studies would suggest that pelvic radiation plus hydroxyurea improves the rate of survival in patients with Stage IIB cervical cancer.

Adult↗

PubMed1979

Inhibition of DNA repair in ultraviolet-irradiated human cells by hydroxyurea.

The effect on DNA repair in ultraviolet-irradiated human skin fibroblasts by hydroxyurea has been examined in this study using three independent methods for measuring DNA repair:the 5-bromodeoxyuridine photolysis assay which measures DNA repair replication, chromatographic measurement of thymine-containing dimers, and measurement of specific ultraviolet-endonuclease-sensitive sites in irradiated DNA. Little effect of hydroxyurea was observed at the concentration of 2 mM, which is often used to inhibit semiconservative DNA synthesis; however, 10 mM hydroxyurea resulted in marked inhibition (65--70%) of excision repair. This inhibition was accompanied by a possible doubling in the size of the repaired region. The accumulation of large numbers of single-strand breaks following ultraviolet irradiation and hydroxyurea incubation seen by other investigators was not observed with the normal skin fibroblasts used in this study. A comparison of hydroxyurea effects on the different DNA repair assays indicates inhibition of one step in DNA repair also results in varying degrees of inhibition of other steps as well.

Bromodeoxyuridine↗

PubMed1988

Relationships between reversion of hydroxyurea resistance in hamster cells and the co-amplification of ribonucleotide reductase M2 component, ornithine decarboxylase and P5-8 genes.

Hydroxyurea is a specific inhibitor of ribonucleotide reductase, which is a rate-limiting enzyme activity in DNA synthesis. Cells selected for resistance to hydroxyurea contain alterations in ribonucleotide reductase activity. An unstable hydroxyurea resistant population of hamster cells has been used to isolate a stable drug resistant cell line, and two stable revertant lines with different sensitivities to hydroxyurea cytotoxicity and different ribonucleotide reductase activity levels. We show for the first time that a decrease in hydroxyurea resistance is accompanied by a parallel decline in gene copies for the M2 component of ribonucleotide reductase, ornithine decarboxylase and a gene of unknown function called p5-8, indicating that the co-amplification of the three genes is associated with drug resistance, and supporting the concept that M2, ornithine decarboxylase and p5-8 are closely linked, and form part of a single amplicon in hamster cells.

Animals↗

PubMed1990

EPR studies on the oxidation of hydroxyurea to paramagnetic compounds by oxyhemoglobin.

N. Hydroxyurea forms methemoglobin from oxyhemoglobin with concomitant formation of the aminocarbonylaminooxyl radical H2N-CO-NHO., as detected with electron paramagnetic resonance spectroscopy (EPR). This radical could be detected for several hours in a low steady-state concentration. Approximately 1 hr after the reaction had been started, the EPR spectra of two additional paramagnetic intermediates could be detected at low temperature (77 degrees K), a low-spin ferric methemoglobin complex with hydroxyurea (MetHb-NHOH-CO-NH2) and the hemoglobin-nitric oxide adduct (Hb2(+)-NO). The intensities of their EPR spectra increased steadily over the range of more than 64 hr. The low-spin ferric methemoglobin complex was immediately formed when hydroxyurea was dissolved in a methemoglobin whereas the nitric oxide complex was possibly an oxidation product of the MetHb-hydroxyurea adduct. Its oxidative degradation is known to lead to the very toxic compounds nitric oxide and nitrogen dioxide which can therefore contribute to the toxic action of hydroxyurea.

Animals↗