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PubMed2004

Analysis of Epstein-Barr virus gene expression upon phorbol ester and hydroxyurea treatment by real-time quantitative PCR.

Epstein-Barr virus (EBV) has the potential to undergo latent and lytic pathways during infection. However, expression of many of the viral genes during the lytic-latent transition remains unclear. In this study, we investigated the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and hydroxyurea (HU), two commonly used modulators of EBV life cycle, on the expression profiles of the entire genome of EBV persistent infected in B95-8 cells. After treatment with TPA for 48 h, the copy number of EBV genome in the cells increased about 2.5 fold, whereas HU treatment resulted in a reduction to approximately two-thirds of the original level. Except a small set of genes, the amounts of EBV mRNA are generally less abundant than that of beta-actin. The expression of a large fraction of the 80 EBV genes was found to be activated after TPA treatment with a noticeable increase of 19 and 21 fold, respectively in BSLF1 and BBLF4. In contrast, treatment of the B95-8 cells with HU, a nucleotide synthesis inhibitor, dramatically suppressed the expression of EBV lytic genes. In summary, we have demonstrated that real-time quantitative PCR is a reliable method to monitor the influence of drug-treatment in EBV genes regulation. Our results also provide a basis for further investigation on how the virus coordinates its own gene expression during latent-lytic pathway transition.

Animals↗

PubMed2002

Spinal meningioma during hydroxyurea therapy. A paradoxycal case report.

We report the case of a 65-year-old woman who developed symptoms of spinal cord compression due to a spinal meningioma after 10 years of treatment with hydroxyurea (1000 mg/day) for essential thrombocytemia. This case provides a paradigm for the occurrence of symptomatic meningioma in course of HU therapy.

Aged↗

PubMed2006

Cytotoxic and genotoxic monitoring of sickle cell anaemia patients treated with hydroxyurea.

Very satisfactory results have been obtained with the treatment of sickle cell anaemia with hydroxyurea (HU), an antineoplastic drug. This is because it significantly increases the levels of foetal haemoglobin. Nevertheless, inadequate dosages or prolonged treatment with this pharmaceutical can provoke cytotoxicity or genotoxicity, increasing the risk of neoplasia. We monitored patients under treatment with HU for possible mutagenic effects, through cytogenetic tests (mitotic index and chromosome aberrations) for one year. Checking at two-month intervals, the cytotoxic effect was not evident. There was no evidence of genotoxicity under the conditions of our experiment. However individuals treated with HU should be constantly monitored, as an absence of genotoxicity could be transitory; the mitotic index should also be observed, as an indicator of cytotoxicity.

Adolescent↗

PubMed2005

Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study.

PURPOSE: Treatment of recurrent and progressive meningiomas remains a challenge in clinical neurooncology. This study was designed to evaluate the efficacy of the simultaneous application of 3d-conformal radiotherapy and chemotherapy with hydroxyurea (HU). PATIENTS AND METHODS: Twenty-one patients with recurrent or progressive meningiomas (13 benign, 4 atypical and malignant, 4 with unproven histology) received treatment by fractionated 3d-conformal radiation (55.8-59.4 Gy) and concurrent HU, administered for a median time of three months with a daily dosage of 20 mg/kg. Response was evaluated using clinical and neuro-imaging data. RESULTS: Disease stabilization was achieved in 14/21 patients (pts). Three pts had significant improvement of tumor associated neurological symptoms with imaging criteria of minor response. Progression free survival rates 1 year and 2 years after the initiation of radio-chemotherapy were 84% and 77%, respectively. At the time of analysis a total of 6/21 pts presented with progressive disease with a median time to progression of 59 weeks. Documented radio- and chemotherapy associated toxicity was minimal; only one patient discontinued HU treatment due to gastrointestinal symptoms such as anorexia and weight loss. CONCLUSION: Results obtained in this study indicate that treatment with HU and simultaneous radiotherapy is safe and effective with disease stabilization in the majority of patients. Randomized trials comparing radiosurgery versus radiochemotherapy versus fractionated radiotherapy are warranted.

Administration, Oral↗

PubMed1977

Concomitant hydroxyurea and irradiation. Clinical experience with 100 patients with advanced head and neck cancer at Pennsylvania hospital.

One hundred outpatients with proved advanced epidermoid carcinoma of the head and neck underwent complete treatment with concomitant hydroxyurea and irradiation therapy. Seventy-three patients exhibited complete regression of the tumor. All patients became candidates for operation after completion of combination therapy, although not all patients accepted surgery.

Carcinoma, Squamous Cell↗

PubMed1984

Hydroxyurea has the capacity to induce damage to human erythrocytes which can be modified by radical scavengers.

The treatment of human erythrocytes with hydroxyurea [HU] results in the azide-dependent changes in osmotic fragility and in increased methemoglobin formation. Similar changes were induced by H2O2 treatment. However when H2O2 in the presence of azide stimulated malondialdehyde production, in the HU-treated cells no malondialdehyde was detectable. When subjected to an oxidant stress [sodium ascorbate] HU-treated erythrocytes were more fragile and revealed changes in the absorption spectrum of the TBA-reactive material in comparison with the cells treated with ascorbate alone. Partial protection by radical scavengers against certain HU-induced changes can be achieved. The results indicate that HU can damage erythrocytes and suggest the radical origin of these effects.

Ascorbic Acid↗

PubMed1984

Deoxyribonucleoside triphosphate pools in human diploid fibroblasts and their modulation by hydroxyurea and deoxynucleosides.

Deoxyribonucleoside triphosphate (dNTP) pool levels were examined in synchronized and unsynchronized log phase cultures and in quiescent cultures of human diploid foreskin fibroblasts. dNTP levels were in good agreement with those previously published for human HeLa and lymphoblastic leukemia cells. dCTP and dGTP levels showed only a modest lowering in quiescent as compared to log-phase cells, but dATP and dTTP levels were reduced dramatically in quiescent cultures. Cells synchronized by serum starvation and assayed at the peak DNA synthetic phase (18-21 hr post release) showed substantially higher pools of all four dNTPs. Hydroxyurea treatment reduced only purine dNTPs in both log phase and confluent cells while increasing dTTP and dCTP pools. The effects of deoxynucleosides on dNTP pools were also examined and are discussed in light of current models regarding regulation of purified ribonucleotide reductase formulated from in vitro studies.

Cells, Cultured↗

PubMed1987

Potentiation of ara-C induced cytotoxicity by hydroxyurea in LoVo colon carcinoma cells.

The present study was undertaken to determine whether cytotoxicity by 1-beta-D-arabinofuranosylcytosine (ara-C) in LoVo colon carcinoma cells, which are resistant to high concentrations of ara-C, would be enhanced by concurrent exposure to hydroxyurea (HU). Since mechanisms underlying the effects of HU on ara-C induced cytotoxicity are unclear, we also evaluated the effect of HU on the incorporation of ara-C into DNA, as well as potential consequences of misincorporation. Our results demonstrate that HU synergistically enhances cytotoxicity by ara-C in these cells. This effect was not present when HU was combined with aphidicolin, an agent that resembles ara-C in competing with dCTP for binding to polymerase alpha but that is not incorporated into DNA. Further, cells exposed to HU and ara-C incorporated up to 5-fold as much ara-C into DNA as cells solely treated with ara-C. While the extent of inhibition of DNA synthesis was comparable with cells exposed to HU and aphidicolin as those treated with HU and ara-C, recovery of DNA synthesis was delayed more significantly by the latter combination. These findings suggest that HU synergistically potentiates ara-C induced cytotoxicity by enhancing incorporation of ara-C in LoVo cell DNA.

Aphidicolin↗

PubMed1988

Differential modulation of 1-beta-D-arabinofuranosylcytosine metabolism by hydroxyurea in human leukemic cell lines.

The ability of hydroxyurea (HU) to modulate 1-beta-D-arabinofuranosylcytosine (Ara-C) metabolism was investigated in human leukemic cell lines. Exposure of HL-60 cells to 1 mM HU enhanced the accumulation of Ara-CTP up to 2.5-fold, whereas HU did not have significant effects on Ara-C metabolism in CEM cells. In addition, two adenine nucleosides, deoxyadenosine (dAdo) and 9-beta-D-arabinofuranosyladenine (Ara-A), which are known to be activated by deoxycytidine (dCyd) kinase as Ara-C, were more effectively phosphorylated after the addition of HU only in HL-60 cells. However, the changes of intracellular dCTP and TTP pools induced by HU, i.e. decrease in dCTP and increase in TTP, were the same in both cell lines. Finally, dCyd production under normal culture conditions was at least 3- to 4-fold higher in HL-60 cells and was inhibited significantly by HU administration. These results suggest that the modulation of Ara-C metabolism by HU occurs at the level of dCyd kinase through the regulation of de novo dCyd generation.

Arabinofuranosylcytosine Triphosphate↗

PubMed1995

Enhancement by hydroxyurea of the anti-human immunodeficiency virus type 1 potency of 2'-beta-fluoro-2',3'-dideoxyadenosine in peripheral blood mononuclear cells.

Ribonucleotide reductase inhibitors such as hydroxyurea (HU) and related compounds, at low, non-toxic doses, enhance the anti-human immunodeficiency virus type 1 (HIV-1) potency of both purine and pyrimidine 2',3'-dideoxynucleosides (ddNs) in human lymphocytes and macrophages. The most marked enhancement of inhibition of HIV-1 replication reported to date has been seen with the purine ddN 2',3'-dideoxyinosine (ddIno): a low level of HU (0.1 mM) permitted a 4.5-fold reduction in optimal ddIno dosage with no decrease in therapeutic effect or increase in toxicity. We report here even more marked enhancement by HU of the potency of the purine ddN 2'-beta-fluoro-2',3'-dideoxyadenosine (2'-beta-F-ddAdo), where the addition of 0.1 mM HU permitted a 7.1-fold reduction in the optimal dose of 2'-beta-F-ddAdo in the phytohemagglutinin-activated peripheral blood mononuclear cell HIV-1 test system.

Antiviral Agents↗

PubMed1975

Inhibitory effect of hydroxyurea on [3-H]leucine incorporation in human peripheral lymphocytes.

Hydroxyurea (HU), generally considered to be a specific inhibiter of DNA synthesis, has an inhibitory effect on the incorporation of TCA-precipitable [3-H]leucine in peripheral lymphocytes. This action is not secondary to the inhibition of DNA synthesis since incorporation of [3-H]leucine is unaffected when DNA synthesis is inhibited by 5-fluorodeoxyuridine (FUdR); it does not appear to be directly related to inhibition of RNA synthesis; and it is not mediated at the level of translation since HU has no effect on protein synthesis in rabbit reticulocytes. The relevance of these findings to the use of HU as a DNA inhibitor is discussed.

Animals↗

PubMed1991

Aspirin blocks 5-azacytidine- and hydroxyurea-induced changes in hemoglobin proportions in adult rats.

The effects of 5-azacytidine and hydroxyurea on their independent ability to change adult hemoglobin proportions toward newborn proportions in adult rats were examined. The results revealed that both the chemotherapeutic agents were capable of switching certain hemoglobin components toward newborn values and required similar time-span to express their actions. However, the switching effect of these drugs was totally lost if aspirin was simultaneously administered into the rats, reflecting the need for concurrent prostaglandin synthesis.

Age Factors↗

PubMed1987

Deoxyribonucleoside triphosphate metabolism and the mammalian cell cycle. Effects of hydroxyurea on mutant and wild-type mouse S49 T-lymphoma cells.

DNA precursor synthesis can be blocked specifically by the drug hydroxyurea (HU) which has therefore been used for anticancer therapy. High concentrations of HU, however, affect other processes than DNA synthesis; nevertheless, most studies on the biological action of HU have been made with concentrations at least one order of magnitude higher than those needed for cell-growth inhibition. In this study we characterized the effects of low concentrations of HU (i.e. concentrations leading to 50% inhibition of cell growth in 72 h) on cell cycle kinetics and nucleotide pools in mouse S49 cells with various defined alterations in DNA precursor synthesis. The effect of 50 microM HU on deoxyribonucleoside triphosphate pools was a 2-3-fold decrease in the dATP and dGTP pools, with no change in the dCTP pool and a certain increase in the dTTP pool. Addition of deoxycytidine or thymidine led to a partial reversal of the growth inhibition and cell-cycle perturbation caused by HU, and was accompanied by an increased level of the deoxyribonucleoside triphosphates. Addition of purine deoxyribonucleoside gave no protection, indicating that salvage of these nucleosides could not supply precursors for DNA synthesis in T-lymphoma cells. We observed a higher sensitivity to HU of cells lacking purine nucleoside phosphorylase or with a ribonucleotide reductase with altered allosteric regulation. Cells lacking thymidine kinase or deoxycytidine kinase were just as sensitive as wild-type cells.

Animals↗

PubMed1988

An in vivo study on the synchronizing effect of hydroxyurea.

The effect of hydroxyurea (HU; 0.5 mg/g body wt) on L 1210 ascites tumor cells has been studied using various cell kinetic methods. In contrast to the general assumption that HU blocks cells at the G1/S boundary [J. Brachet (1985) Molecular Cytology, Vol. I, p. 266, Academic Press, New York], the present results show that the cells are not held at G1/S but enter S at about the normal rate and are accumulated in early S phase due to a dose-dependent inhibiting effect of HU on DNA synthesis. Partial synchronization of the cells demonstrated by a distinct mitotic peak 10 h after HU application is not due to a G1/S block of the cells and their subsequent synchronous passage through the cycle after release from the block but is due to rather complex mechanisms of action of HU: a differential cytocidal effect and an effect on the passage of the cells through the cycle, both depending on the position of the cells throughout the cycle. HU kills S-phase cells, mainly cells in early S phase; i.e., a great portion of the cells "accumulated" in early S phase is killed by the drug, while G1-phase cells are almost not affected by the lethal effect of HU. These G1-phase cells pass through the cycle more rapidly after cessation of the HU effect. The same is true for the surviving cells accumulated in early S phase, while part of the cells in the remaining S phase are delayed in their passage through the cycle. This causes partial synchronization, since a great portion of all cells that survive HU treatment reach mitosis at the same time.

Animals↗

PubMed1983

Toxoplasma gondii: genetic crosses reveal phenotypic suppression of hydroxyurea resistance by fluorodeoxyuridine resistance.

Mutants resistant to sinefungin (SF) and hydroxyurea (HU) were isolated from an oocyst-producing strain of Toxoplasma gondii with the aid of mutagenesis with ethylnitrosourea. These mutants were used with previously described mutants resistant to adenine arabinoside (araA) and fluorodeoxyuridine (FUDR) in genetic crosses in cats. In order to interpret the data from crosses in which all four mutants were used to infect the same cat, it was necessary to devise a mathematical expression to predict the recombination frequency for unlinked markers. This frequency was shown in theory to be half of the product of the two parental phenotype frequencies. A series of crosses in which the parental frequencies were systematically varied yielded frequencies of recombination that were in accord with this calculation. The four-way crosses in the same cat showed unlinked recombination between all markers except HU and FUDR. This pair of markers yielded no doubly resistant recombinants, suggesting complete linkage. However, linkage was excluded when a binary cross between the HU- and FUDR-resistant mutants resulted in the normal number of doubly sensitive recombinants. The lack of doubly resistant recombinants was shown to be a consequence of phenotypic suppression of HU resistance by FUDR resistance. This suppression was first demonstrated by showing that an FUDR-resistant mutant selected from an HU-resistant parasite lost the HU resistance. The phenotypically suppressed HU-resistant gene was revealed by genetic crosses with wild type T. gondii. Although both parental stains were sensitive to HU, some of the progeny parasites were resistant.

Animals↗

PubMed1992

Compartmentation of dCTP pools disappears after hydroxyurea or araC treatment in lymphocytes.

The calculated rate of DNA synthesis using [5-3H]TdR was about 4 times higher than in the case of [5-3H]CdR labeling, even after correction for the specific radioactivities of the intracellular pools. These data show a compartmentation of dCTP pools in lymphocytes. Hydroxyurea increased the specific activities of both dTTP and dCTP pools so that the calculated rate of DNA synthesis became equal. The same effect was found for araC treatment, but not for fluorodeoxyuridine. dCTP was supplied from CTP which is the lowest ribonucleotide pool in lymphocytes. Different functions of the two dCTP pools are proposed: one serving DNA replication; the other one supplies phospholipid precursors and DNA repair.

Cytarabine↗

PubMed1978

Enhancement of repair replication in mammalian cells by hydroxyurea.

The effect of hydroxyurea on DNA repair replication has been studied in Chinese hamster ovary cells. Mitotic cells were treated with UV irradiation, methyl methanesulfonate or nitrogen mustard and incuated in the presence of each of the 4 [3H] deoxyribonucleosides plus BrdUrd and FdUrd for 2 h. The amount of repair replication was quantitated on CsCl gradients and similar values were obtained for each nucleoside. In all cases addition of HU during the incubation period increased these values approximately 2-fold. Following MMS treatment, pool sizes for each of the nucleosides were estimated by varying the amount of exogenously supplied nucleoside. They were found to be insensitive to the addition of HU and it is concluded that the increased incorporation of [3H]deoxyribonucleosides in the presence of HU reflects an increased amount of repair replication.

Cell Line↗

PubMed1980

The effect of hydroxyurea and mitomycin C on sperm motility in mice.

The mutagen, mitomycin C, and the teratogen, hydroxyurea, were found to decrease sperm motility in mice in a dose-dependent manner. Positive results with these compounds suggest that sperm motility may have been decreased through either mutations or developmental disturbances. Sperm motility can be determined quickly and may be done in conjunction with a sperm-morphology assay.

Animals↗