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PubMed1988

DNA replication in Syrian hamster cells transiently exposed to hydroxyurea.

DNA rereplication has been observed in mammalian cells transiently treated during S phase with hydroxyurea, an inhibitor of DNA synthesis. Recently, evidence has been presented which does not support this proposal. We have performed a series of similar but more defined studies with the tumorigenic Syrian hamster cell line BP6T to further investigate the possibility of DNA rereplication after transient inhibition during S phase. Synchronized BP6T cells (greater than 75%) were given a 6-h exposure to 1 mM hydroxyurea after having progressed 2 h into S phase. The DNA species synthesized up to 24 h after removal of the inhibitor have been identified by bromodeoxyuridine pulse labeling and density gradient centrifugation studies. The results indicate that no DNA rereplication had occurred in the S phase of the same cell cycle as the transient hydroxyurea treatment. DNA replicated early in the S phase in which treatment was given was not replicated again until the next cell cycle. Our observations reveal that DNA rereplication does not occur in tumorigenic Syrian hamster cells transiently insulted with hydroxyurea during S phase. Thus, these findings imply that DNA synthesis is stringently controlled in these transformed cells.

Animals↗

PubMed1986

Changes of deoxyribonucleoside triphosphate pools induced by hydroxyurea and their relation to DNA synthesis.

Hydroxyurea inactivates ribonucleotide reductase from mammalian cells and thereby depletes them of the deoxynucleoside triphosphates required for DNA replication. In cultures of exponentially growing 3T6 cells, with 60-70% of the cells in S-phase, 3 mM hydroxyurea rapidly stopped ribonucleotide reduction and DNA synthesis (incorporation of labeled thymidine). The pool of deoxyadenosine triphosphate (dATP) decreased in size primarily, but also the pools of the triphosphates of deoxyguanosine and deoxycytidine (dCTP) were depleted. Paradoxically, the pool of thymidine triphosphate increased. After addition of hydroxyurea this pool was fed by a net influx and phosphorylation of deoxyuridine from the medium and by deamination of intracellular dCTP. An influx of deoxycytidine from the medium contributed to the maintenance of intracellular dCTP. 10 min after addition of hydroxyurea, DNA synthesis appeared to be completely blocked even though the dATP pool was only moderately decreased. As possible explanations for this discrepancy, we discuss compartmentation of pools and/or vulnerability of newly formed DNA strands to nuclease action and pyrophosphorolysis.

Cells, Cultured↗

PubMed1986

Neutrophil depletion of calves with hydroxyurea: methods and clinical and pathologic effects.

Twenty-six Holstein calves were treated with hydroxyurea in order to induce neutropenia. Calves were given a daily dosage of hydroxyurea (70 mg/kg of body weight) for 4 consecutive days, and clinical signs, blood leukograms, hemograms, and platelet counts were monitored daily until the calves became neutropenic. Once a neutropenic state was induced, the calves were anesthetized and pulmonary function tests were performed. Subsequently, calves were euthanatized and complete necropsies were performed. Hydroxyurea treatment induced profound neutropenia in all calves by 8 days after initiating treatment, with mild decreases in circulating numbers of lymphocytes. Treatment did not cause clinical or pulmonary functional abnormalities. Severe pathologic changes were restricted to the bone marrow and consisted of partial to complete destruction of myeloid elements, with less severe effects on erythrocytic precursors and megakaryocytes. Hydroxyurea was useful for the induction of neutropenic states in calves and did not induce major toxic effects on other cells when given at 70 mg/kg.

Agranulocytosis↗

PubMed1985

Hydroxyurea interferes negatively with triglyceride measurement by a glycerol oxidase method.

Measured triglyceride concentrations were extremely low (less than 100 mg/L) in the serum of some patients who were receiving hydroxyurea for myeloproliferative diseases. The assay being used to quantify triglycerides was a "cascaded" enzymatic method involving (a) lipase, to generate glycerol from triglycerides; (b) glycerol oxidase, to convert glycerol to glyceraldehyde, with generation of hydrogen peroxide; and (c) peroxidase, which acts on the hydrogen peroxide with subsequent coupled generation of a red-violet quinone (reagent system used in the Technicon RA-1000). Hydroxyurea added to serum samples appeared to inhibit the action of glycerol oxidase, with a stoichiometric relation to the concentration of substrate (a decrease of roughly 2.4 mmol/L in measured triglyceride per 1 mmol of hydroxyurea per liter). A different enzymatic assay for triglycerides, which involves glycerol kinase (Beckman Instruments) did not show this effect of hydroxyurea.

Autoanalysis↗

PubMed1985

Increased gene amplification in L5178Y mouse lymphoma cells with hydroxyurea-induced chromosomal aberrations.

Chromosomal aberrations and dihydrofolate reductase gene amplification are observed in L5178Y mouse lymphoma cells after treatment with hydroxyurea. The types of aberrations include polyploidy, endoreduplication, chromosome fragmentation, and the presence of extrachromosomal DNA. Hydroxyurea-treated cells analyzed by cell sorting showed a subpopulation of cells with increased DNA and increased dihydrofolate reductase. This subpopulation shows a high incidence of chromosome aberrations and an increased frequency of dihydrofolate reductase gene amplification. Hydroxyurea-treated cells with the normal amount of DNA and dihydrofolate reductase have few aberrations and a low frequency of dihydrofolate reductase gene amplification. We propose that hydroxyurea treatment causes overreplication of DNA and that recombination of overreplicated DNA can lead to chromosome aberrations and gene amplification.

Animals↗

PubMed1983

Combined cytotoxic effect of low-dose 5-fluorouracil and hydroxyurea on 9L cells in vitro.

Continuous exposure of exponentially growing 9L rat brain tumor cells for 24 hr to a nontoxic dose (0.77 microM) of 5-fluorouracil (5-FUra) produced a progressive increase in S-phase cells from 35% (asynchronous culture) to 70% as shown by DNA histograms based on data obtained by flow cytometry. When 9L cells were treated with the S-phase-specific agent hydroxyurea (1.3 mM) immediately after treatment with 5-FUra, a synergistic cell kill resulted. A centrifugal elutriation study confirmed that enhanced cell kill was caused in part by the S-phase synchrony produced by 5-FUra and to the S-phase specificity of hydroxyurea. A higher dose (7.7 microM) of 5-FUra caused a partial G1-S block; subsequent treatment with hydroxyurea also enhanced cell kill, but the enhancement was not related to S-phase synchrony. A centrifugal elutriation study suggested that, after 24-hr treatment with 5-FUra, hydroxyurea might kill both cells in S phase, which has the greater number of clonogenic cells, and kill cells that are in other phases of the cell cycle, including cells blocked at the G1-S border that are vulnerable to the phenomenon of "thymidineless death"; concomitant administration of thymidine along with 5-FUra eliminated enhanced cell kill.

Animals↗

PubMed1983

Effect of hydroxyurea on neural tube defects in the curly-tail mouse.

Around 60% of curly-tail mice spontaneously develop neural tube defects (NTD), that is, exencephaly, and/or spina bifida (open lesions), or a curly tail (closed lesion), due to an incompletely penetrant recessive gene. Various doses of hydroxyurea, a teratogen to the rodent central nervous system, were administered to curly-tail mice on either day 8 or day 9 of pregnancy in an attempt to increase the number of NTD in the embryos. No dose used on either day achieved this. However, on day 8, the proportion of affected mice with open lesions increased from around 30% in control mice to 78% with 400 mg/kg hydroxyurea, and this was accounted for specifically by the production of exencephaly. When administered on day 9, 400, 500, and 600 mg/kg hydroxyurea (the latter two doses being lethal to embryos on day 8) actually reduced the incidence of total NTD, to around 30%. Among these affected mice, even though reduced in number, there was still a slight tendency for an increase in the number of exencephalics. Hydroxyurea also produced gastroschisis in a small percentage of embryos; the greatest incidence was 36% with 400 mg/kg on day 8.

Animals↗

PubMed1994

Efficacy of alpha interferon and hydroxyurea in late phase refractory myeloproliferative disease.

Three patients are described with late-stage myeloproliferative diseases, two with accelerated phase chronic myelogenous leukemia (CML) and one with refractory polycythemia vera (P vera), who achieved hematologic control after the addition of interferon (IFN) to hydroxyurea therapy. Both the CML patients continue to have a sustained clinical remission at 12 and 38 months. The patient with P vera had failed several previous treatments including busulfan, P32, hydroxyurea, and anagrelide, but became responsive after interferon use followed by reintroduction of hydroxyurea. Our observations support the efficacy of IFN alpha and hydroxyurea combination in late-phase myeloproliferative disease and warrants further clinical investigation.

Adult↗

PubMed1993

Indications, procedure and results for the treatment of polycythaemia vera by bleeding, pipobroman and hydroxyurea.

The present report is based on an analysis of the evolution of 720 cases of Polycythaemia vera treated with pipobroman and 624 cases treated with hydroxyurea. General modes of treatment are identical for the two drugs, consisting of initial therapy at relatively high dose aimed at obtaining complete remission and maintenance therapy essential to conserve the improved clinical status. Both types of treatment must be adapted to suit the patient. Complete remission is achieved in 95 to 100% of cases with pipobroman and in 80 to 90% of cases with hydroxyurea. Incidents which may occur during initial therapy include cytopenia, more frequent and severe under treatment with hydroxyurea, rare transitory digestive troubles and cutaneous and mucous eruptions. Subject to control of the blood cell count every three to four months, maintenance therapy may be continued for many years and while the time lapse is as yet insufficient for hydroxyurea, resistance to pipobroman does not appear to develop even after more than 20 years of treatment. Although neither of these two drugs entirely avoids the occurrence of acute leukaemia which appears in 5 to 8% of subjects irrespective of the duration of therapy, on the contrary to observations in patients treated by bleeding alone, myeloid splenomegaly with myelofibrosis is rare and develops in no more than 2% of cases. The frequency of visceral cancers is not increased by either drug. Provided Polycythaemia vera is maintained in complete remission, thrombotic accidents occur no more often than in a normal population of the same age bracket.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1996

[A lower-leg ulcer during hydroxyurea therapy for essential thrombocythemia].

A skin ulcer of the lateral malleous developed in a 61-year-old man receiving hydroxyurea for essential thrombocythemia. In the past, skin ulcers have been reported in patients with chronic myeloproliferative diseases, including essential thrombocythemia, who had been treated with hydroxyurea. In the current case, vasculitis or thrombi in vessels of the biopsied specimen of the lower leg were not observed, and the patient required skin-graft operation. Accordingly, we concluded that the skin ulcer might be due to the administration of hydroxyurea. Thus, the dose of hydroxyurea was decreased.

Foot Ulcer↗

PubMed1996

Dual modulation of 5-fluorouracil with folinic acid and hydroxyurea in metastatic colorectal cancer.

Leucovorin and 5-fluorouracil (5-FU) can be further modulated with hydroxyurea. Sixty-eight patients with advanced colorectal cancer received every 2 weeks hydroxyurea per os 1.5 g to 2 g days -1, 1, and 2; leucovorin 200 mg/m2 iv over 2 hours started at least 1 hour after hydroxyurea and per os 100 mg/m2 12 hours later, on days 1 and 2; 5-FU, bolus 400 mg/m2 during leucovorin infusion and 24 hours continuous infusion 600 mg/m2, repeated on days 1 and 2. Two complete responses (7%), 8 partial responses (30%), 12 no change (44%), and 5 progressions (19%) were observed among 31 nonpreviously treated patients. Four partial response (11%), 15 no change (43%), and 16 progressions (46%) were observed among 37 pretreated patients. Nineteen were treated after progression on the same regimen without oral leucovorin and hydroxyurea, 1 achieved PR and 10 showed no change. Among them, 6 experienced response or stabilization of longer duration than with previous treatment. Twelve-month survival was 61% in non-pretreated and 43% in pretreated patients as of the start of chemotherapy. Toxicity was mild with nausea in 46%, diarrhea in 37%, and mucositis in 36%. The first-line response rate is in the range of leucovorin and 5-FU alone. Some pretreated patients benefited from this regimen.

Adenocarcinoma↗

PubMedDate not supplied

Hydroxyurea in the treatment of HIV-1 infection: toxicity and side effects.

Hydroxyurea has been used in numerous clinical trials for the treatment of HIV-1 infection, almost always in combination with didanosine with or without other antiretrovirals. Due to its inhibition of DNA synthesis, the main side effect of hydroxyurea is myelosuppression. When administered at the dosage of 1000 mg/day in asymptomatic, moderately-immunosuppressed HIV-1 infected patients, its tolerability profile appears to be quite favourable, with rare, reversible episodes of peripheral blood cytopenia that seldom require therapy discontinuation. Higher dosages of hydroxyurea and its use in advanced, heavily-pretreated patients may increase the likelihood of more severe side effects or newer toxicities developing. So far hydroxyurea-containing long therapy courses, up to 3 years, have not elicited any significant toxicity and appear to be safe as in onco-hematologic patients.

Anti-HIV Agents↗

PubMed1999

Mechanism of Differentiation of HEL Cells Induced by Hydroxyurea.

HEL cells, a human erythroleukemia cell line, mainly express fetal globin gene(gamma) and small amount of the embryonic(epsilon) globin gene, but not the adult (beta) globin gene. Our previous studies demonstrated that hydroxyurea could induce HEL cells to express adult (beta) globin gene and induce HEL cells to terminal differentiation. In order to reveal the differentiation mechanism of HEL cells induced by hydroxyurea, GMSA was performed to examine the binding of nuclear extracts from hydroxyurea induced and uninduced HEL cells to the positive control region in the 5'-flanking sequence of human beta-globin gene and to the synthesized GATA oligonucleotides. Our results showed that, in the nuclear proteins from the induced HEL cells, the binding of GATA-1 to GATA motif was increased. However, the binding of GATA-2 to GATA motif was decreased. Besides, our data showed that a YY1-like protein was decreased quickly in hydroxyurea induced HEL cells. Western blotting analysis was used to analyze variation of GATA proteins in nuclei of HEL cells. Results revealed that the amount of GATA-2 was significantly decreased while the amount of GATA-1 was increased after HEL cells were induced for 12 h. These results indicate that GATA-1 may play a critical role in inducing HEL cells to terminal differentiation. The YY1-like protein and GATA-2 might inhibit HEL cells from terminal differentiation.

Journal Article↗

PubMed1998

Early cutaneous lesions secondary to hydroxyurea therapy.

Hydroxyurea is a usually well-tolerated cytostatic agent, but its side effects include cutaneous lesions that appear after several years of maintenance therapy with hydroxyurea. The reported incidence of such adverse reactions varies from 10 to 35%; in our Center it is 2%. We describe a patient with essential thrombocythemia who presented with ulcers of the hands only 15 days after hydroxyurea treatment.

Aged↗

PubMed2001

Behcet's disease in a patient with chronic myelogenous leukemia under hydroxyurea treatment: a case report and review of the literature.

Behcet's disease (BD) is a chronic, relapsing vasculitis of unknown etiology. Its association with chronic myelogenous leukemia (CML) is extremely rare, and typical manifestations of BD were observed in a very few patients with CML, mainly under interferon-alpha (IFN-alpha) treatment. Skin pathergy test, being positive in about 50% of patients with BD, is also positive in some IFN-alpha-treated patients with CML without any evidence of BD symptoms. We describe a 62-year-old woman with CML who developed characteristic features of BD, including a positive skin hyperactivity test, during treatment with hydroxyurea. Hydroxyurea has been implicated in the appearance of skin vasculitic ulceration, but this is the first case, according to our knowledge, where the development of BD was observed during hydroxyurea maintenance in the chronic phase of CML.

Antineoplastic Agents↗

PubMed1980

Studies of hydroxyurea administered by continuous infusion: toxicity, pharmacokinetics, and cell synchronization.

Hydroxyurea was administered by means of two schedules designed to provide continuous 72-hour exposure of tumor cells to therapeutic drug levels. Toxicity and pharmacokinetics were determined for both an oral pulse dose schedule (every 4 hours x 18 doses) and continuous intravenous (IV) infusion for 72 hours. The maximal tolerated dose (MTD) was 800 mg/m2 every 4 hours for the oral route and 3.0 mg/m2/min x 72 hours for IV infusion. Granulocytopenia was dose-limiting for both schedules and correlated well with plasma-HU levels. Serial sampling of normal bone marrow (10 patients) and tumor tissue (3 patients) showed a modest degree of synchronization induced by continuous IV infusion of hydroxyurea. Interindividual pharmacokinetic variations severely limit the usefulness of the oral pulse schedule as a potential means of synchronizing cells. Hydroxyurea administered by continuous IV infusion may be useful as a synchronizing agent in humans.

Administration, Oral↗

PubMed1982

Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia.

Survival of patients with chronic myeloid leukemia seen in the University of Colorado Leukemia Clinic were reviewed with respect to therapy. A total of 55 patients seen consecutively through mid 1980 were included in this study. Of these patients 30 were treated with busulfan, 14 were treated with hydroxyurea and 11 received under modalities. Busulfan treated patients who are now deceased, have had a median survival of 35 months (range, 13-108) and actuarial analysis shows the total busulfan treated population to have an expected median survival of 48 months. Hydroxyurea treated patients who are still alive have been followed for a median period of 69 months (range, 25-136 months) and a projected median survival for periods of 56 and 90 months, respectively. These data suggest that hydroxyurea may be an important treatment modality in the treatment of chronic myelogeous leukemia.

Adolescent↗

PubMed1983

Hydroxyurea fails to improve the results of MBD chemotherapy in cancer of the head and neck, but reduces toxicity.

Thirty-six patients with advanced squamous cancer of the head and neck received chemotherapy with hydroxyurea, 2 g/m2 orally two of three weeks, plus methotrexate, bleomycin, and cisplatin (MBD) on a previously established schedule. Nineteen patients had objective responses, including six complete remissions. Eight of 13 patients with regional disease without prior radiation responded, as did 1 of 3 with distant metastases without prior radiation, and 10 of 20 with recurrent disease after radiotherapy. The median duration of response in those with recurrent or metastatic tumor was 6 months, and median survival was 6.5 months. These results are no better than those previously achieved without the addition of hydroxyurea. Toxicity, however, was milder than had previously been observed with MBD, suggesting that higher doses or more intensive schedules of hydroxyurea could be safely administered together with the other three drugs.

Adult↗