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PubMed1996

Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas.

OBJECTIVE: To determine the efficacy of the combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas after failure of either previous radiotherapy alone or previous radiotherapy plus nitrosourea-based chemotherapy. METHODS: Seventy-seven patients with recurrent malignant gliomas were studied. 6-Thioguanine was administered for 4 days before lomustine, and procarbazine was administered for 1 day before and 2 days after lomustine to potentiate lomustine's antitumor effect. Hydroxyurea was initiated 1 day before lomustine and continued for a total of 3 days. RESULTS: Thirty patients with glioblastomas and 47 patients with anaplastic gliomas were eligible for evaluation. In the glioblastoma group, 2 of 30 patients had a partial response and 8 of 30 patients had stable disease. This group of patients who responded and had stable disease included 6 of 10 patients who had not undergone previous chemotherapy but only 4 of 20 who had undergone previous chemotherapy. The overall median time to disease progression for the glioblastoma group was 9 weeks. In the anaplastic glioma group, 11 of 47 patients had a partial response and 25 of 47 had stable disease, including 23 of 30 without previous chemotherapy and 13 of 17 who had undergone previous chemotherapy. The median time to disease progression for the whole anaplastic glioma group was 24 weeks; however, the time to disease progression was 50 weeks for responding patients who had not undergone previous chemotherapy and 25 weeks for those who had undergone previous chemotherapy. CONCLUSION: Our results indicate that chemotherapy with a combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea is active for patients with recurrent anaplastic gliomas and glioblastomas not previously treated with nitrosourea-based chemotherapy but is inactive for patients with glioblastomas previously treated with chemotherapy.

Adolescent↗

PubMed2005

Parents' assessment of risk in sickle cell disease treatment with hydroxyurea.

Hydroxyurea is the only medication shown to reduce the severity of sickle cell disease (SCD), but its long-term risks are unknown. Families of 58 children with SCD were interviewed on their perception of the potential risks of hydroxyurea treatment, and whether disease severity was a major factor in their treatment decision. Parents rated the severity of their child's SCD (86% as severe, 26% moderate, and 47% mild) and then the highest levels of risk that they would tolerate for both potential cancer (range 1/1,000 to 1/2) and potential birth defects (range 1/1,000 to 1/3) to benefit their child with hypothetical hydroxyurea treatment. Parents of 29 of the 58 children were unwilling to take any cancer risk whatsoever as a potential side effect of treatment, and 29 of 58 (not all the same parents) were unwilling to take any risk for birth defects, including half the children with severe SCD. For those families who did accept some risk, higher acceptable risk correlated with higher disease severity in the child (P = 0.04). The study's mixed findings highlight the complexities of risk perception and suggest that future studies of risks and benefits from the parental viewpoint are needed as candidate therapies are developed for SCD.

Abnormalities, Drug-Induced↗

PubMed2003

Blue lunula due to hydroxyurea.

Alteration in the color of lunula can be an indication of either a cutaneous or systemic disorder or a systemic drug side effect. Hydroxyurea, an antitumor systemic agent (a ribonucleoside diphosphate reductase inhibitor) used in the treatment of refractory psoriasis as well as in the variety of neoplastic disorders is known to cause brownish pigmentation of the nails but hydroxyurea induced blue lunula is very rare. It is being reported in a 45-year-old man with chronic recalcitrant plaque psoriasis on oral hydroxyurea 500 mg twice daily. Lunular pigmentation in finger and toenails developed two weeks later. During follow up, pigmentation remained localized to the proximal portion of nails.

Antineoplastic Agents↗

PubMed1993

Hydroxyurea treatment for chronic myeloid leukaemia during pregnancy.

A patient being treated for chronic myeloid leukaemia with hydroxyurea became pregnant. Despite an increase in the dose of hydroxyurea (to 3 g per day) during the pregnancy, her white blood cell count could only be controlled at about 150 x 10(9)/l. A healthy baby girl was born at 37 weeks with normal blood counts and no evidence of congenital abnormality. There are now five reports of the use of hydroxyurea in pregnancy, and where leukapheresis is not available it may be the treatment of choice.

Adult↗

PubMed1987

Hydroxyurea: effects on deoxyribonucleotide pool sizes correlated with effects on DNA repair in mammalian cells.

We have measured deoxyribonucleotide pool sizes in different cell types: normal human, transformed human (HeLa), and the permanent hamster line CHO-K1. The range of sizes of the four DNA precursor pools in CHO cells is far greater than in human cells. It is a general rule that hydroxyurea causes rapid depletion of pools (except for dTTP) until the pool present in smallest amount is exhausted; this suggests a tight coupling of the pools to DNA replication (the presumed main cause of the depletion). The effect of hydroxyurea on DNA repair after ultraviolet irradiation (namely, a relatively small accumulation of incomplete repair sites blocked at the resynthesis stage) is probably accounted for by the reduced availability of DNA precursors. However, depletion of the dCTP pool is not an adequate explanation for the observed enhancement by hydroxyurea of the inhibitory effect of cytosine arabinoside; we suggest other possible modes of action. Ultraviolet irradiation has only small effects on the levels of deoxyribonucleotides.

Animals↗

PubMed1989

Hydroxyurea increases the phosphorylation of 3'-fluorothymidine and 3'-azidothymidine in CEM cells.

The triphosphates of the nucleoside analogues 3'-azidothymidine and 3'-fluorothymidine inhibit reverse transcriptase and are of therapeutic interest for the treatment of retrovirus infections. At equimolar concentrations 3'-fluorothymidine was more effectively transformed to the triphosphate by human CEM cells than azidothymidine which mainly accumulates as the monophosphate. Hydroxyurea, a drug that inhibits de novo synthesis of deoxyribonucleotides, considerably increased the ability of cells to phosphorylate both analogues. Addition of as little as 50 microM hydroxyurea decreased the amount of dideoxynucleoside required to attain a given intracellular concentration of its triphosphate by an order of magnitude. Hydroxyurea is known to shift the balance of substrate cycles between natural deoxynucleosides and their 5'-phosphates in the direction of synthesis and thereby to increase the import and intracellular phosphorylation of the nucleoside. The present results demonstrate a similar effect for the two analogues and raise the possibility of using this effect in therapy.

Antiviral Agents↗

PubMed1988

Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea.

A total of 59 symptomatic patients with myeloproliferative disorders (polycythaemia vera 24 pats., essential thrombocythaemia 25 pats., myelofibrosis 10 pats.) and elevated platelet counts were studied during 1653 months of continuous treatment with hydroxyurea. Reduction of the platelet level to less than 500 x 10(9)/l was achieved within 8 weeks in 86% of polycythaemia pats., 80% of thrombocythaemia pats., 60% of myelofibrosis pats. Control of disease-related symptoms was achieved within 1 year in 78% of the patients. There was no instance of severe bone marrow toxicity. Side-effects of hydroxyurea were modest. Survival was excellent, with 86% probability of survival after 5 yr of therapy. We consider hydroxyurea a first-choice alternative in the treatment of patients with polycythaemia vera, essential thrombocythaemia and mylofibrosis with thrombocytosis.

Drug Evaluation↗

PubMed1998

Hydroxyurea therapy in thalassemia.

The clinical effectiveness of Hydroxyurea in thalassemia is still controversial. The present paper puts together the authors' experience in two groups of patients with thalassemia intermedia and sickle cell/beta-thalassemia treated with varying dosages of hydroxyurea over several months. A third group received hydroxyurea along with recombinant human erythropoietin. Our observations are summarized in that treatment with hydroxyrea results in a significant increase of fetal hemoglobin with no change of the total hemoglobin levels. The drug causes also a considerable increase of the erythrocyte volume and hemoglobin content while the MCHC values remain unchanged. As a rule, and without objective criteria so far, patients state feeling better and having more energy. The authors postulate that this feeling may reflect the significant decrease of ineffective erythropoiesis resulting by the replacement of the poorly hemoglobinized, prematurely dying erythroid progenitor and red cell population by another population of cells with higher hemoglobin content and longer survival, the regeneration of which requires less energy and consumption. As expected, patients with sickle cell/beta-thalassemia have also fewer crises and painful episodes. The above findings are in keeping with the few available reports in the literature.

Anemia, Sickle Cell↗

PubMed1973

Reversible inhibition of herpes simplex virus replication by hydroxyurea.

Hydroxyurea, at a concentration of 5 x 10(-2) M, inhibits the replication of herpes simplex deoxyribonucleic acid (DNA) in the nuclei of infected cells. As a result, the synthesis of infectious virus progeny was prevented. The presence of parental viral DNA genomes in inhibited cells led to the synthesis of the viral structural peptides. The inhibitory effect of hydroxyurea was reversible; after washing the cells free from hydroxyurea, virus progeny appeared after a lag of 3 h. Upon resumption of viral DNA replication, the content of radioactive viral structural peptides gradually increased in parallel with the increase in mature virions. It is concluded that the information for the synthesis of viral structural peptides is transcribed from the parental DNA genomes.

DNA, Viral↗

PubMed1973

Studies on the developmental cycle of Chlamydia trachomatis: selective inhibition by hydroxyurea.

Hydroxyurea, a potent inhibitor of deoxyribonucleic acid synthesis, inhibits the development of trachoma agent when applied at a concentration of 5 x 10(-2) M. At a lower concentration, 5 x 10(-4) M, hydroxyurea permits the development of the trachoma inclusion bodies and initial bodies, but arrests the formation of elementary bodies, the infectious entity of the agent. The inhibitory effect of 5 x 10(-4) M hydroxyurea is reversible and can be used to synchronize the development of the agent. The synthesis of deoxyribonucleic acid, ribonucleic acid, and proteins takes place in the initial bodies after the removal of the inhibitor.

Amino Acids↗

PubMed1973

Hydroxyurea-induced accumulation of short fragments during polyoma DNA replication. I. Characterization of fragments.

Hydroxyurea treatment of 3T6 mouse fibroblast cells infected with polyoma virus resulted within 15 min in more than a 20-fold reduction of the rate of both viral and cellular DNA synthesis. After the initial rapid inhibition, the rate of DNA synthesis remained essentially constant for at least 2 h. In the inhibited cells viral DNA accumulated as short chains with a sedimentation coefficient of about 4S (hydroxyurea fragments). A variable proportion of these fragments was released from the template strands when the viral DNA was extracted by the Hirt procedure. Reannealing experiments demonstrated that hydroxyurea fragments were polyoma-specific and probably synthesized on both parental strands at the replication forks.

Animals↗

PubMed1983

Enhancement of methotrexate resistance and dihydrofolate reductase gene amplification by treatment of mouse 3T6 cells with hydroxyurea.

We investigated various parameters associated with the initial selection of mouse 3T6 cells for resistance to single concentrations of methotrexate and characterized resistant colonies for the presence of additional (amplified) copies of the dihydrofolate reductase gene. Our results indicate that the frequency of occurrence of dihydrofolate reductase gene amplification varies with the selecting concentration of methotrexate and is highly variable between clonally derived sublines of mouse 3T6 cells. Second, we increased the frequency of occurrence of cells with amplified dihydrofolate reductase genes by transiently inhibiting DNA synthesis with hydroxyurea before the selection of cells in single concentrations of methotrexate. This effect was dependent on the concentration of hydroxyurea, the time of exposure to the drug, and the time interval between the removal of hydroxyurea and the selection of cells in methotrexate.

Animals↗

PubMed1972

Long-term effects of hydroxyurea in psoriases.

Hydroxyurea is an effective treatment for psoriasis but consistently produces macrocytosis in peripheral blood with a fall in haemoglobin levels and white cell counts. In this long-term study of 16 patients anaemia and leukopenia have proved frequent and troublesome side effects requiring discontinuance of treatment in many cases. In view of these findings hydroxyurea cannot be recommended as the drug of first choice even for treating severe and intractable psoriasis, and it is our opinion that methotrexate is safer and at least as effective in these circumstances. The clearest indications for the use of hydroxyurea appear to be in life-ruining psoriasis when methotrexate treatment has either failed or is contraindicated because of liver damage. A great deal more investigative work is required before these indications can be generally extended.

Adult↗

PubMed1987

Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells.

We have shown previously that cDNAs for the M1 and M2 subunits of ribonucleotide reductase, ornithine decarboxylase (ODC), and p5-8, a 55,000-Dalton protein, hybridize to amplified genomic sequences in a highly hydroxyurea-resistant hamster cell line. We have extended these observations to include two additional, independently isolated, hydroxyurea-resistant cell lines: SC8, a single-step hamster ovary cell line, and KH450, a multistep human myeloid leukemic cell line, have also undergone genomic amplification for sequences homologous to ODC and p5-8 cDNAs. However, neither SC8 nor KH450 contains amplified genomic sequences homologous to an M1 cDNA probe. A panel of mouse-hamster somatic cell hybrids was used to map sequences homologous to M1, M2, ODC, and 5-8 cDNAs in the hamster genome. The M2, ODC, and p5-8 cDNAs hybridized to DNA fragments that segregated with hamster chromosome 7. In contrast, M1 cDNA hybridized to DNA fragments that segregated with hamster chromosome 3. These data suggest that the genes RRM2, (M2), ODC, and p5-8, but not RRMI (M1), are linked and may have been co-amplified in the selection of the hydroxyurea-resistant hamster and human cell lines.

Animals↗

PubMed1991

[Multicenter prospective controlled study of therapy of chronic myeloid leukemia. Comparison of busulfan, hydroxyurea and interferon alpha (April 1990 status)].

In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon alpha instead of busulfan prolongs the chronic phase of Philadelphia-positive CML. Additional goals are the examination, 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 September 5, 1990, 593 CML-patients had been randomized, 221 for busulfan, 228 for hydroxyurea and 144 for interferon alpha. The average age is about 51 years. By April 30, 1990, 106 patients had reached the end of the chronic phase, 126 had died. The median survival of Philadelphia-positive patients was 3.95 years, that of all patients 3.75 years. The median observation time of all patients was 1.34 years (mean 1.60 years). At present, no significant difference in survival is recognizable between the three treatment arms, although fewer adverse effects have been observed in the hydroxyurea arm.

Busulfan↗

PubMed1984

Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.

Hydroxyurea, a widely used cytotoxic/cytostatic agent that does not influence methylation of DNA bases, increases fetal hemoglobin production in anemic monkeys. To determine its effect in sickle cell anemia, we treated two patients with a total of four, 5-d courses (50 mg/kg per d, divided into three oral doses). With each course, fetal reticulocytes increased within 48-72 h, peaked in 7-11 d, and fell by 18-21 d. In patient I, fetal reticulocytes increased from 16.0 +/- 2.0% to peaks of 37.7 +/- 1.2, 40.0 +/- 2.0, and 32.0 +/- 1.4% in three successive courses. In patient II the increase was from 8.7 +/- 1.2 to 50.0 +/- 2.0%. Fetal hemoglobin increased from 7.9 to 12.3% in patient I and from 5.3 to 7.4% in patient II. Hemoglobin of patient I increased from 9.0 to 10.5 g/dl and in patient II from 6.7 to 9.9 g/dl. Additional single-day courses of hydroxyurea every 7-20 d maintained the fetal hemoglobin of patient I t 10.8-14.4%, and the total hemoglobin at 8.7-10.8 g/dl for an additional 60 d. The lowest absolute granulocyte count was 1,600/mm3; the lowest platelet count was 390,000/mm3. The amount of fetal hemoglobin per erythroid burst colony-forming unit (BFU-E)-derived colony cell was unchanged, but the number of cells per BFU-E-derived colony increased. Although examination of DNA synthesis in erythroid marrow cells in vitro revealed no decreased methylcytidine incorporation, Eco RI + Hpa II digestion of DNA revealed that hypomethylation of gamma-genes had taken place in vivo after treatment. This observation suggests that hydroxyurea is a potentially useful agent for the treatment of sickle cell anemia and that demethylation of the gamma-globin genes accompanies increased gamma-globin gene activity.

Adolescent↗

PubMed2000

A pilot study of low dose hydroxyurea as a novel resistance modulator in metastatic renal cell cancer.

Mechanisms of chemoresistance in renal cell carcinoma include P-glycoprotein, overexpression of multidrug resistance-1 (mdr1) gene, and unstable chromosomal aberrations. In vitro exposure of resistant tumor cells to low dose hydroxyurea causes loss of chromosomal aberrations, decrease in the mdr1 gene copies, and increased sensitivity to vinblastine. Patients received continuous hydroxyurea 500 mg every Monday, Wednesday and Friday. Vinblastine 5 mg/m2 was given intravenously on days 1 and 8 every 21 days. Seventeen patients with a median age of 63 (range 40-80) received a median of 3 courses of vinblastine (range 1-14). Toxicities included: > or = grade 3 non-hematologic toxicity (1) and febrile neutropenia (2). No treatment related mortality occurred. Three patients (17.6%) had partial responses. The median survival was 38.0 weeks (95% CI = 26.9-49.1 weeks). The addition of hydroxyurea given at the dose of 500 mg orally three times weekly had no major impact on the expected antitumor effect of vinblastine.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2002

Hydroxyurea corrects the dysregulated L-selectin expression and increased H(2)O(2) production of polymorphonuclear neutrophils from patients with sickle cell anemia.

Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n = 15); (2) patients with a history of vasoocclusive events (n = 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n = 9). Unstimulated PMNs showed decreased L selectin expression and increased H(2)O(2) production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H(2)O(2) production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H(2)O(2) production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H(2)O(2) production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug.

Adolescent↗