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PubMed1999

Combined prenatal toxicity of 6-mercaptopurine riboside and hydroxyurea in mice.

Hydroxyurea (HU) and 6-mercaptopurine riboside (6-MPr) are used as cytostatic chemotherapeutics. Their teratogenic potential in experimental animals has been well known for several decades. Generally, it is assumed that the toxicity of both agents is due to an interference with enzymes of DNA synthesis. In the case of 6-MPr, it was speculated that the teratogenicity in rodents might be paralleled by or even correlated to an incorporation of 6-thioguanine into the DNA of the embryos. In this study, the interaction between these two compounds with regard to teratogenicity in NMRI mice was investigated. Dose-response data of 6-MPr (s.c.-treatment) were published earlier. First, a dose-response study with HU alone (i.p.-treatment) was performed. From these data, the doses for the combination study were derived: HU 250 mg/kg (NOAEL dose) and 6-MPr 16 mg/kg (strongly teratogenic dose). In all experimental groups the substances were administered to the dams once on day 11 of gestation. Combination effects were investigated applying various dosing regimens. In group I treatment was simultaneous, in group II HU was administered 2 h before 6-MPr, in group III 2 h after 6-MPr. The differences in the overall frequency of gross structural abnormalities were moderate. However, when analysing the effects in more detail (single abnormalities), group III exhibited great differences: 1) 6-MPr co-treatment increased the frequency of HU effects (skull defects) and 2) HU co-treatment decreased the frequency of 6-MPr effects (limb defects) when compared to the findings of the dose-response studies. In addition, the influence of HU on the 6-MPr-induced DNA modification was determined by measuring the incorporation of 6-thioguanine into the DNA of day-11 embryos. As expected, the HU co-treatment corresponding to the group III dosing regimen of the teratogenicity experiment decreased the incorporation rate by ca. 40%. This was in parallel to the decrease in the frequency of 6-MPr effects in the teratogenicity III group. This finding may be considered as a further indication that in the case of 6-MPr, DNA modification is accompanying teratogenicity.

Abnormalities, Drug-Induced↗

PubMed1999

An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology.

Because there are differing opinions regarding treatment of patients in the chronic phase of chronic myeloid leukemia (CML), the American Society of Hematology convened an expert panel to review and document evidence-based benefits and harms of treatment of CML with busulfan (BUS), hydroxyurea (HU), recombinant interferon-alpha (rIFN-alpha), and bone marrow transplantation (BMT). The primary measure for defining efficacy was survival. Analysis indicated a survival advantage for HU over BUS. Observational studies of rIFN-alpha suffer from numerous biases including sample size, variations in study populations, definitions of hematologic and cytogenetic remissions, and dose. That rIFN-alpha is more efficacious than chemotherapy is demonstrated by 6 prospective randomized trials. For patients with favorable clinical features in chronic phase, compared to HU and BUS, rIFN-alpha improves survival by a median of about 20 months. Most evidence suggests that rIFN-alpha is most effective when combined with other drugs and when given during the earliest stage of the chronic phase. Adding cytarabine to rIFN-alpha adds further survival benefit but increases toxicity. Limitations for evaluating the long-term benefits of allogeneic BMT include the retrospective nature of most studies, incomplete documentation of the clinical characteristics of the patients, paucity of the details on patient selection, lack of control groups, and limitations of survival calculations. Survival curves for BMT show that at least half of the patients transplanted remain alive 5 to 10 years after treatment, whereas similar curves for rIFN-alpha show a continuous relapse rate over time with the curves crossing at about 7 to 8 years. Estimates of long-term survival may be confounded by the selection biases mentioned and the analytic methods used. The magnitude of the incremental increase in benefit with BMT must be weighed against the potential serious harm and death that may accompany the procedure in the short term. The best results with BMT have been obtained when it is performed within 1 to 2 years from diagnosis. Since each treatment option involves tradeoffs between benefit and harm, patient choice must be based on the examination of facts presented in an unbiased fashion. Newly diagnosed younger patients and older patients who are candidates for BMT should also be offered information about IFN-based regimens, the tradeoffs involved, and, if possible, share in the treatment decision. Hopefully this analysis will provide the stimulus for evaluation of other important aspects of CML.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease.

Children with sickle cell disease (SCD) and stroke receive chronic transfusions to prevent stroke recurrence. Transfusion risks including infection, erythrocyte allosensitization, and iron overload suggest a need for alternative therapies. We previously used hydroxyurea (HU) and phlebotomy in two young adults with SCD and stroke as an alternative to transfusions. We have now prospectively discontinued transfusions in 16 pediatric patients with SCD and stroke. Reasons to discontinue transfusions included erythrocyte alloantibodies or autoantibodies, recurrent stroke on transfusions, iron overload, noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d based on hematologic toxicity. Patients with iron overload underwent phlebotomy. The children have been off transfusions 22 months, (range, 3 to 52 months). Their average HU dose is 24.9 +/- 4.2 mg/kg/d, hemoglobin concentration is 9.4 +/- 1.3 g/dL, and mean corpuscular volume (MCV) is 112 +/- 9 fL. Maximum percentage fetal hemoglobin (%HbF) is 20.6% +/- 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% +/- 14.7%. Fourteen patients underwent phlebotomy with an average of 8,993 mL (267 mL/kg) removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had neurological events considered recurrent stroke, each 3 to 4 months after discontinuing transfusions, but before maximal HU effects. These preliminary data suggest some children with SCD and stroke may discontinue chronic transfusions and use HU therapy to prevent stroke recurrence. Phlebotomy is well-tolerated and significantly reduces iron overload. Modifications in HU therapy to raise HbF more rapidly might increase protection against stroke recurrence.

Administration, Oral↗

PubMedDate not supplied

[Effect of hydroxyurea treatment on free nucleotides in leukemic leukocytes].

An increase was observed in the pool of free nucleotides of leukaemic leucocytes during treatment with hydroxyurea, which was used as a drug inducing remission in chronic myeloid leukaemia and as an agent synchronizing the cell cycle in the so-called synchronization treatment of acute myeloid leukaemia. The increase in the amount of free nucleotides may depend on their increased synthesis and on their less extensive utilization for synthesis of nucleic acids. According to the authors the observed changes in the pool of free nucloetides may possess certain therapeutic implications.

Adolescent↗

PubMed2000

Synergistic enhancement of herpes simplex virus thymidine kinase/ganciclovir-mediated cytoxicity by hydroxyurea.

We have previously demonstrated (L. Z. Rubsam et al., Cancer Res., 59: 669-675, 1999) that low ganciclovir (GCV) triphosphate (TP) levels similar to cellular deoxynucleotide concentrations can induce multilog killing in cells stably expressing herpes simplex virus thymidine kinase (HSV-TK). In this study, we evaluated whether reducing the endogenous competitor of GCV-TP, dGTP, enhanced GCV-mediated cytotoxicity. In SW620 human colon carcinoma cells stably expressing HSV-TK, the addition of the ribonucleotide reductase inhibitor, hydroxyurea (HU), decreased cellular dGTP pools and simultaneously increased the accumulation of GCV-TP levels. The amount of GCV nucleotide transfer from HSV-TK-expressing to nonexpressing (bystander) cells was quantitated in physically separated pHook-expressing bystander cells. Elevation of the GCV-TP:dGTP ratio by HU resulted in increased levels of GCV nucleotides transferred from HSV-TK-expressing to bystander cells during a 24 h drug incubation and enhanced GCV monophosphate incorporation into DNA after drug removal. Isobologram analysis demonstrated that the combination of GCV and HU was additive in 100% HSV-TK cultures and synergistic in HSV-TK/bystander mixtures. IC50 values for GCV in 1:1 cocultures of HSV-TK-expressing and nonexpressing SW620 cells were reduced from 1.5 microM to 0.07 microM with 2 mM HU. A similar reduction was also observed with HT-29 cells and U251 cells. With 2 mM HU, IC50 values for GCV in 10:90, 5:95, and 1:99 SW620 HSV-TK-expressing and nonexpressing cocultures were reduced from 55 microM to 0.3 microM, 71 microM to 0.8 microM, and 118 microM to 7 microM, respectively. These results demonstrate the ability to pharmacologically enhance HSV-TK/GCV-mediated bystander killing and may have an important therapeutic impact.

Antineoplastic Agents↗

PubMed2000

Acquired DNA mutations associated with in vivo hydroxyurea exposure.

Hydroxyurea (HU) is an effective therapeutic agent for patients with myeloproliferative disorders (MPDs) or sickle cell disease (SCD). Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been associated with an increased risk of leukemia in some patients with MPD. In this study, 2 assays were used to quantitate acquired somatic DNA mutations in peripheral blood mononuclear cells (PBMCs) after in vivo HU exposure. The HPRT assay measures hypoxanthine phosphoribosyl transferase (hprt) mutations, while the VDJ assay identifies "illegitimate" T-cell receptor Vgamma-Jbeta interlocus recombination events. PBMCs were analyzed from patients with MPD, adults and children with SCD, and normal controls. MPD patients with prolonged HU exposure had numbers of DNA mutations equivalent to patients with low HU exposure or controls. Similarly, adults with SCD had equivalent numbers of DNA mutations regardless of HU exposure. Children with SCD and 30-month HU exposure had equivalent hprt(-) mutations but significantly more VDJ mutations (1.82 +/- 1.20 events per microg DNA) than children with 7-month HU exposure (1.58 +/- 0.87 events) or no HU exposure (1.06 +/- 0.45 events), P =.04 by analysis of variance. Taken together, these data suggest that the mutagenic and carcinogenic potential of in vivo HU therapy is low. Although increased numbers of illegitimate VDJ recombination events do not directly portend leukemia, young patients with SCD and HU exposure should be monitored serially for increases in DNA mutations.

Adult↗

PubMed2000

Hydroxyurea-induced marked oscillations of platelet counts in patients with polycythemia vera.

Two prospectively studied patients with polycythemia vera (PV) whose platelet counts showed marked periodic fluctuation during treatment with hydroxyurea (HU) are reported. Cycle lengths in both were approximately 28 to 30 days. In one patient, the cyclic process was no longer evident when treatment with HU was withheld, and it reappeared on treatment rechallenge. Circulating thrombopoietin (TPO) levels fluctuated out of phase with the platelet count despite markedly reduced TPO-receptor (c-Mpl) expression in bone marrow megakaryocytes. These observations suggest that the cyclic phenomenon may be related to both a transient state of HU-induced depletion of megakaryocytes and a concentration-dependent mitigation by TPO of the HU effect on megakaryocytes and their precursors. It is conceivable that the affected patients harbor a megakaryocyte progenitor pool whose apoptotic activity is differently modulated by either HU or high concentrations of TPO. (Blood. 2000;96:1582-1584)

Antisickling Agents↗

PubMed2000

[Hydroxyurea and HIV infection].

Hydroxyurea is an anticancerous product, used recently in the treatment of HIV-1 infection thanks to its inhibitory action in viral replication, potentialization of the nucleosides activity (particularly ddI or didanosine) and its cytostatic properties on CD4 and CD8 lymphocytes. Many studies showed its efficiency, as further drug, in initial regimen of a tritherapy (containing ddI) and salvage therapy. The dosage of 500 mg bid seems tolerated well by adults, and 20 mg/kg by children. Long-term tolerance remains unknown. With ddI, it could be proposed in developing countries.

Adult↗

PubMed1975

Manganese mutagenesis in yeast. IV. The effects of magnesium, protein synthesis inhibitors and hydroxyurea on AntR induction in mitochondrial DNA.

The induction of antibiotic-resistant mutations in yeast mitochondrial DNA by manganese is decreased when the manganese-containing medium is additionally supplemented with magnesium. At equimolar concentrations of manganese and magnesium the former is no longer mutagenic. Amino acid starvation, cycloheximide, chloramphenicol and erythromycin have very little, if any, effect on the mutagenicity of manganese. Hydroxyurea itself seems to be slightly mutagenicity of manganese. Our results show that manganese acts as an error-producing factor in DNA replication probably through a direct interaction with mitDNA polymerase(s).

Cell Division↗

PubMed2000

[Anhidrosis during long-term hydroxyurea therapy in a patient with chronic myelogenous leukemia].

A 62-year-old man was diagnosed as being in the chronic phase of chronic myelogenous leukemia (CML) in 1990, and subsequently treated with hydroxyurea (HU). The total HU dose administered reached 2,929 g (average, 1.44 g/day). In December 1995, the patient was admitted to our hospital for control of the CML. Following HU therapy, he often experienced high fever (38-39 degrees C) due to infection or blastosis, and at that time his skin showed marked pigmentation, dryness and scaling with itching and anhidrosis. A skin biopsy sample from the left scapula showed atrophic change of the skin and epidermal tissues with fibrotic changes and damage to the subcutaneous glands. This was strongly suspected to have been caused by the continuous HU administration, and the anhidrosis and dryness was considered to have contributed to the patient's high body temperature. Frequent cooling of the patient's body was effective.

Antineoplastic Agents↗

PubMed2001

[Hydroxyurea-induced leg ulcers in patients with chronic myeloproliferative disorders].

INTRODUCTION: Hydroxyurea (HU) is usually a well-tolerated antineoplastic agent, which is commonly used in the treatment of myeloproliferative disorders. Dermatological abnormalities are often seen in patients receiving long-term HU therapy. Leg ulcers have been reported occasionally. MATERIAL AND METHODS: We carried out a prospective and descriptive study of patients who developed leg ulcers while receiving HU therapy. RESULTS: Between 1.1.1997 and 1.2.1998, chronic cutaneous leg ulcers were found in five out of a total of 28 patients treated with HU. The average age was 76 years (64-87 years). Two patients had chronic myelogenous leukaemia in a non-accelerated phase, two polycytaemia vera, and one essential thrombocytosis. The average duration of HU therapy was 30 months (10-55 months) before ulcerations appeared. These were typically located on the malleolar and/or perimalleolar area, and were very painful. HU therapy was discontinued and replaced by busulphan or anagrelide. Within 1.5-11 months of discontinuation of the treatment, the wounds had healed or improved. DISCUSSION: We found a surprisingly high number of cutaneous leg ulcers in patients on HU therapy for chronic myeloproliferative disorders. We believe this disabling complication should be given greater attention and recommend that it is included in the description of the side effects of the drug.

Aged↗

PubMed2000

[Effect of hydroxyurea combined with interferon-alpha on growth and apoptosis-related oncogene expression of K562 cells].

OBJECTIVE: To observe the effect of hydroxyurea (HU) alone and in combination with interferon-alpha (IFN-alpha) on the cell growth and cell death, and the related oncogene expression of chronic myelogenous leukemia (CML) cell line, K562 cells. To further investigate the molecular basis of combination therapy on CML by chemotherapeutants combined with cytokines. METHODS: The proliferation and viability of K562 cells were detected by cell-counting and trypan blue dye exclusion test. The levels of bcr-abl, bax and c-myc gene expression in K562 cells incubated for 48 hours were examined using RT-PCR technique. RESULTS: proliferation was suppressed and cell death process was accelerated by both HU and HU combined with IFN-alpha. HU significantly inhibited bcr-abl gene expression and increased bax gene expression level (both P < 0.05 as compared with that of control). Furthermore, IFN-alpha dose-dependently enhanced the regulatory effects of HU on bcr-abl and bax gene expression. HU alone and in combination with IFN-alpha suppressed slightly c-myc gene expression. CONCLUSIONS: Both HU and HU combined with IFN-alpha can inhibit cell proliferation and promote cell death or apoptotic cell death by regulating the expression levels of the genes relating to cell proliferation and apoptosis. The molecular mechanism of HU and IFN-alpha synergistically acting on leukemic cells is further elucidated from the expression level of the related genes which control the balance of survival and death or apoptosis of the cells.

Apoptosis↗

PubMedDate not supplied

Role of hydroxyurea during structured treatment interruptions.

Highly active antiretroviral therapies (HAART) represent a major advance in the treatment of HIV infection. Although with HAART a substantial suppression of viral replication can be obtained, eradication of the virus from the body cannot be achieved. Therefore, HIV-infected subjects have to be treated for the rest of their lives. Long term treatment will increase the frequency of: i) drug-related side effects; ii) onset of drug-resistant viral strains; iii) non-adherence of the patients to the treatment. Structured treatment interruptions (STI)-HAART might represent a feasible alternative and preliminary studies have shown that STI-HAART might induce immune control in patients treated in the early stage of infection. This regimen does not produce similar effects in patients treated during the chronic phase of the infection. However, there are some clinical data suggesting a possible role of hydroxyurea (HU) in inducing control of HIV replication in patients with established infection. In this manuscript in vitro and in vivo data indicating that HU might play a major role in the setting of STI-HAART will be presented.

Adult↗

PubMedDate not supplied

Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells.

Gemcitabine (Gem) is a deoxycytidine analogue whose active metabolite, dFdCTP, blocks DNA elongation and has a cytotoxic effect. Hydroxyurea (HU) is an S-phase specific inhibitor of ribonucleotide reductase (RR) with a broad spectrum of antitumor effects. We report here that low-dose HU enhanced the activity of Gem in a time- and sequence-dependent manner. Exposure of human oropharyngeal carcinoma KB cells to HU followed by the addition of Gem at various times significantly enhanced cytotoxicity when compared to controls. The greatest enhancement of cytotoxicity occurred when Gem was added 8 hours after HU. By treating KB cells with radiolabeled-Gem following HU treatment, we further confirmed that the incorporation of dFdCTP into DNA increased 6-fold over control reactions under these conditions. The mechanism of the time- and sequence-dependent enhancement is associated with a decrease in hRRM2 RNA, protein, and activity between 4 and 8 hours. The subsequent depletion of dNTP pools allows for increased incorporation of dFdCTP into cells arrested in S-phase, resulting in higher levels of cytotoxicity than either treatment alone.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

The activity of superoxide dismutase in hydroxyurea-treated E beta thalassemia.

AIM: To study the activity of superoxide dismutase (SOD) and the level of fetal hemoglobin (HbF) in hydroxyurea (HU)-treated E beta thalassaemia. METHODS: We have measured SOD level, HbF, mean corpuscular volume (MCV), packed cell volume (PCV) and hemoglobin (Hb) of E beta thalassaemia treated with HU (dose 30 mg/kg/day) for consecutive 90 days. RESULT: The increase of HbF synthesis without increase of Hb was observed in HU-treated patients. CONCLUSION: The decreased SOD level in long term and low dose of HU therapy in E beta thalassaemia may have some role to inhibit superoxide radical of erythrocyte. HU may act as inhibitor for oxidative damage of red cell in E beta thalassaemia.

Adolescent↗

PubMedDate not supplied

Dermatomyositis-like eruption after long-term hydroxyurea therapy for polycythemia vera.

Hydroxyurea (HU) is an antitumor agent used to treat chronic myeloproliferative disorders. HU is usually well tolerated, but several cutaneous changes have been reported during long-term HU therapy. Although the occurrence of dermatomyositis-like changes during long-term HU therapy are well known, they are rarely described in patents with polycythemia vera. We report a 69 year-old-male with polycythemia vera who developed a dermatomyositis-like eruption on his face and dorsum of the hands following long-term HU therapy. Despite the cutaneous features, there were no clinical signs of muscular involvement, and muscle specific enzymes were within normal ranges. After interruption of HU administration, the skin lesions disappeared within two months. The improvement following withdrawal of HU implicated this drug as a possible etiological factor in the development of cutaneous features of dermatomyositis in our patient.

Aged↗

PubMed2003

[Effect of hydroxyurea on hemoglobin S].

Previous studies have determined the laboratory alterations, clinical efficacy and toxicity profile associated with hydroxyurea (HU) therapy in patients with severe sickle cell anemia. We report the efficacy of HU treatment in the prevention of vaso-occlusive crises in an 11-years-old boy with severe sickle cell disease. The number of vaso-occlusive crises, hospital days and blood transfusions in the year before HU treatment were compared with the same parameters at 6, 12, 24, 36 and 72 months of treatment. A decrease in the frequency of vaso-occlusive crises, blood transfusions and days spent in hospital were demonstrated during the HU treatment period compared to the same period before hand. The clinical and laboratory response to HU was dramatic in this severely affected patient, allowing him a normal schooling and social life. The adverse effects observed were not serious and reversed after transient discontinuation of HU. We conclude that long-term chronic treatment with HU for seriously ill sickle cell patients appears feasible, and devoid of any major toxicity.

Anemia, Sickle Cell↗

PubMed1976

[Anticonidiogenic effect of hydroxyurea on Neurospora crassa].

Conidiation induced in a low sugar-ammonium medium (or by other means such as full starvation or heat shock) is almost fully prevented by hydroxyurea. In a parallel manner the DNA/RNA and DNA/protein ratios are prevented from increasing.

Cell Differentiation↗