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PubMed1978

Effects of hydroxyurea on murine type C virus-specific DNA synthesis in newly infected cells.

Cell transformation and replication of the Rauscher pseudotype of Moloney murine sarcoma virus in mouse embryo fibroblasts were inhibited by hydroxyurea within a critical time period of 30 to 90 min postinfection. In cells infected by Rauscher leukemia virus, treatment with 1mM hydroxyurea during the critical time period resulted in the accumulation of minus-strand DNA (molecular weight, 3 x 10(6)) in association with the parental viral genoma RNA. This 5 to 6 x 10(6) dalton RNA:DNA hybrid was found in the cytoplasm. Positive-strand DNA of genomic or smaller size was not detected in the presence of hydroxyurea, but virus-specific DNA was found in the nucleus 30 min after removal of drug.

Cell Transformation, Neoplastic↗

PubMed1982

Inhibitors of bacterial urease: microbiological considerations on hydroxyurea influenza virus.

Hydroxyurea is a well known enzyme urease inhibitor. Bacteria strains producers of enzyme urease can be the cause of struvite calculosis. Clinical studies have shown that treatment with hydroxyurea can produce acid urine in patients suffering from struvite calculosis. In this work antiurease and antibacterial activity of hydroxyurea was valued in vitro against Proteus mirabilis strains. Our results seem not to agree with the ones obtained in vivo.

Escherichia coli↗

PubMed1983

Schedule dependence of vincristine lethality in Sarcoma 180 cells following partial synchronization with hydroxyurea.

The effects of exposure to 0.1, 0.5, or 2 microM vincristine for 4 hr were studied in Sarcoma 180 cells at various times after synchronization with 5 mM hydroxyurea for 1 hr. Maximum sensitivity to the lethal effects of vincristine was observed at 10 to 14 hr after hydroxyurea exposure at the higher vincristine concentrations, compared to a period of a maximum sensitivity to a second dose of hydroxyurea at 8 to 12 hr. Serial flow cytometry studies indicated that the apparent decrease in sensitivity to vincristine at 14 to 18 hr was due to the division of cells in the leading segment of the synchronized wave and their entry into the relatively resistant G1 phase prior to vincristine exposure. Synchronized cells that had not divided at the time of vincristine exposure were blocked transiently in G2. Serial metaphase index studies suggested that the G2 cells closest to the end of the cell cycle at the time of vincristine exposure were likely to exhibit the greatest degree of mitotic disorganization when they overcame the G2 block and entered metaphase. The present studies suggest that sensitivity to vincristine increases progressively as cells approach mitosis. The molecular mechanisms underlying this phenomenon are considered in relation to the increase in cell tubulin content during the course of cell cycle progression.

Animals↗

PubMed1982

Stem cell (CFUs) proliferation inhibitor in blood of mice injected with hydroxyurea.

Analysis of the mouse haemopoietic stem cell (CFUs) kinetics after hydroxyurea administration has provided an in vivo assay suitable for detection of factors which inhibit recruitment of non-proliferating G0-CFUs into cell cycle, or transit of CFU's through the G1 phase. Using this assay, it has been demonstrated that plasma obtained from mice which had received hydroxyurea approximately 12-14 hr previously, possesses a factor which inhibited the triggering of CFUs into the cell cycle. The appearance of this CFUs proliferation inhibitor occurred at a time when 60-70% of the CFUs were synchronized in the S phase of the cell cycle, as a consequence of hydroxyurea action. Some basic properties of the inhibitor were investigated.

Animals↗

PubMed1981

Fever caused by hydroxyurea.

Hydroxyurea has been rarely implicated as a cause of drug fever. In this report, we describe a patient who was highly febrile while receiving hydroxyurea for psoriasis. The fever disappeared after discontinuation of therapy with this drug; however, the fever recurred when the patient received hydroxyurea again.

Aspirin↗

PubMed1995

[Bilateral ankle ulcers associated with hydroxyurea therapy for chronic myelogenous leukemia].

Bilateral ankle skin ulcers developed in a 61-year-old man in the chronic phase of chronic myelogenous leukemia receiving hydroxyurea therapy. The circulating immune complex (anti-C3d antibody) was high in this case, but vasculitis was not observed in the pathological findings of biopsied skin materials. This association has been reported in patients who had chronic myelogenous leukemia or other myeloproliferative disorders and were treated with hydroxyurea. It is likely that skin ulcers are caused by hydroxyurea.

Foot Ulcer↗

PubMedDate not supplied

Oral cyclophosphamide and oral hydroxyurea in the treatment of hormone refractory prostate cancer in rats.

Hormone refractory prostate cancer is a fatal disease and currently no standard cytotoxic chemotherapy exists for prostate cancer. The recent use of prostate specific antigen as an endpoint for clinical trial has resulted in the ability to test the activity of chemotherapy agents in a quick manner. The aim of this study was to investigate the activity of the oral combination of two familiar agents, cyclophosphamide and hydroxyurea, against hormone refractory prostate cancer. In vitro studies demonstrated that hydroxyurea was more active than cyclophosphamide against the anaplastic Dunning rat prostate cancer cell line, Mat-LyLu. In vivo experiments, however, demonstrated cyclophosphamide to be superior to hydroxyurea. The combination of both agents failed to enhance inhibition of subcutaneously implanted Mat-LyLu cells. A human trial of oral cyclophosphamide using prostate specific antigen as an intermediate endpoint may be warranted.

Adenocarcinoma↗

PubMed1993

[Treatment of hypereosinophilic syndromes of myeloproliferative expression with the combination of hydroxyurea and interferon alpha. Apropos of 7 cases].

Seven patients suffering from hypereosinophilic syndrome with clinical and/or hematological symptoms of a myeloproliferative syndrome were treated with a combination of hydroxyurea and interferon-alpha. To date, 6 of them have been followed for more than 1 year. In all cases, this therapy decreased circulating hypereosinophilia to under 1,500/mm3 and obtained normal eosinophil levels in 5 patients with a parallel regression of visceral complications. None of the patients experienced treatment-associated side effects, particularly hematological ones. Hypereosinophilic syndrome has a poor prognosis due, for the most part, to the development of visceral, cardiac and neurological complications, and, more secondarily, to the risk of progression towards acute leukemia. Conventional treatments, corticosteroids and hydroxyurea, have greatly improved the prognosis, but failure of these therapeutics remains common in the myeloproliferative form of the disease. Because interferon-alpha was proven to effectively treat chronic myeloid leukemia, it has been proposed for the treatment of hypereosinophilic syndromes, and encouraging results have been obtained despite the high daily doses required to control the disease. In the future, its association with hydroxyurea could represent an alternative therapy capable of controlling the disease at low doses thereby limiting the risk of side effects.

Adult↗

PubMed1995

A preliminary evaluation of hydroxyurea for the treatment of rheumatoid arthritis.

OBJECTIVE: To obtain preliminary evidence on the safety and efficacy of low dose hydroxyurea as a treatment for rheumatoid arthritis (RA). METHODS: Five patients with active RA unresponsive to conventional therapy were entered into a 12 week, open label trial of hydroxyurea followed by a one month postdrug evaluation. RESULTS: Three of the 4 patients completing the study had a decrease in morning stiffness and number of swollen and tender joints. All 4 patients had a decrease in pain and an increase in function as measured by a modified health assessment questionnaire. No patient had improvement in sedimentation rate, C-reactive protein, or subjective measures of global well being. However, 3 of the 4 patients had disease flare after the drug was withdrawn, demonstrated by increased number of swollen and tender joints. CONCLUSION: Low dose hydroxyurea may be effective in the treatment of RA, but confirmation will require further testing by a randomized double blind placebo controlled trial of patients with a broader spectrum of disease severity over a longer period of therapeutic intervention.

Adult↗

PubMed1997

Use of hydroxyurea in children with sickle cell disease: what comes next?

Hydroxyurea (HU) is the first drug that, under well-organized clinical trials, has shown the potential for altering significantly the clinical severity of sickle cell disease (SCD). The placebo-controlled trial of HU in adult SS hemoglobinopathy patients (the Multicenter Study of Hydroxyurea in Sickle Cell Anemia) reported in May 1995 that HU therapy reduced significantly the frequencies of severe pain episodes, acute chest syndrome, and transfusion. Despite these impressive results, no guidelines have been developed to direct clinicians on the use of HU in adult SCD patients. Small-scale phase II studies in children have reported increases in fetal hemoglobin (HbF) and F-cell levels in response to HU therapy. A larger phase II study, the Pediatric Hydroxyurea Study Group (HUG-KIDS), is under way and is expected to be completed by March 1998. The need for a large-scale placebo-controlled trial in children will be doubtful if no unusual short-term toxicity is demonstrated by HUG-KIDS. Guidelines regarding patient selection, dosing schedules, treatment goals, and short- and long-term monitoring parameters need to be established. The case is made of the organization of a clinical network to register and follow SCD patients treated with HU for long-term toxicity.

Adult↗

PubMed1976

Differentiation of Herpetomonas megaseliae: effects of hydroxyurea on morphology and growth.

Herpetomonas megaseliae grown in the presence of hydroxyurea showed a decline in population during the first 24 hr, eventually increasing slightly over the 7-day incubation. Throughtout the 7-day incubation period the population of the treated organisms never equaled that of the control organisms. The percentage of promastigotes, as opposed to para-and opisthomastigotes, in the treated cultures did not differ from that in the control cultures through the first 3 days in incubation. Thereafter, the percentage of promastigotes in the treated cultures dropped significantly below that of the controls. At the light microscope level, the treated organisms showed an increase in size with associated striations at the anterior end. A multiflagellate (nondividing) condition was also observed in the hydroxyurea-treated organisms. TEM and SEM studies showed pellicular convolutions, which were interpreted as the striations observed under the light microscope. The differnces in population number, kinetoplast number and position and pellicular morphology between control and experimental cultures suggests that enhanced differentiation and abortive cytokinesis are the net effects of hydroxyurea on Herpetomonas megaseliae.

Animals↗

PubMed2003

Hydroxyurea-induced dermatomyositis-like eruption.

Hydroxyurea is a cytotoxic chemotherapeutic agent used for myelodysplasia. The adverse cutaneous effects due to hydroxyurea include leg ulcers, hyperpigmentation of the skin and nails, a lichen planus-like eruption, lupus erythematosus, and a dermatomyositis-like eruption. We present a case of hydroxyurea-induced dermatomyositis-like eruption and review the features of this entity as previously reported.

Aged↗

PubMed1996

Acute myeloid leukemia evolving from essential thrombocythemia in two patients treated with hydroxyurea.

Essential thrombocythemia (ET) is an uncommon myeloproliferative disorder, which is thought to develop from a multipotent stem cell. Like other myeloproliferative diseases, ET is associated with an increased risk of development of acute leukemia (AL). However, the large majority of cases of leukemic transformation in ET are thought to be related to prior therapy, usually radioactive phosphorous or alkylating chemotherapy, and the development of AL in ET is extremely rare in the untreated patient. In this report, two cases of ET which evolved into AL without prior exposure to radiation or alkylating agents, and which were treated with long-term hydroxyurea therapy, are described. The first case had cytogenetic changes in the bone marrow suggestive of therapy-associated leukemia, and the second developed myelodysplastic syndrome on therapy which was likely chemotherapy-induced and led to acute leukemia. Prolonged used of hydroxyurea in patients with ET may lead to therapy-associated acute leukemia.

Acute Disease↗

PubMed1999

Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature.

A patient being treated for sickle cell disease with hydroxyurea (1 g/d) conceived, and drug treatment was discontinued at nine weeks gestational age. The pregnancy and delivery were complicated by vaso-occlusive crises. A healthy male infant was born at 39 weeks with no evidence of congenital malformations. A literature review, including this case, suggests that the risk of hydroxyurea exposure during in pregnancy may have been overestimated. Further studies are required to determine its safety in pregnancy.

Adult↗

PubMed1999

Comparison of radial immunodiffusion and alkaline cellulose acetate electrophoresis for quantitating elevated levels of fetal hemoglobin (HbF): application to evaluating patients with sickle cell disease treated with hydroxyurea.

Radial immunodiffusion (RID), alkaline cellulose acetate electrophoresis, and high-performance liquid chromatography (HPLC) were compared for quantitating the elevated (> 10%) level of fetal hemoglobin (HbF) found in the red blood cells of sickle cell disease patients undergoing treatment with hydroxyurea. HPLC- and electrophoresis-determined values were comparable. The RID-determined values were higher, in many cases twofold higher. False high HbF values would be misleading in assessing the effectiveness of hydroxyurea therapy in sickle cell disease patients. We subsequently initiated an examination of the variation in HbF values due to the use of different HbF radial immunodiffusion QUIPlates and different positions within a single plate in an attempt to determine the cause of these discrepancies. Within-run precision studies indicated that significantly different size precipitin rings were obtained depending upon which area of the plate the hemolysate containing antigen (HbF) was applied. A common feature associated with poor precision plates was a marked difference in degree of coloration of gel throughout the plate. Spuriously high HF concentrations were obtained with antigen (HbF) placed in wells located in the lighter colored gel area while antigen placed in wells in the darker colored area of the agarose gel bed were more in agreement with the electrophoretically determined HbF concentrations. The variation in HbF values was significantly greater in the diluted (HbF QUIPlate Diluent) samples than in the neat samples even on plates of uniform gel coloration. As a result of this study, we will continue to monitor high HbF levels by densitometry following alkaline cellulose acetate electrophoresis.

Adult↗

PubMed1993

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial.

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.

Adult↗

PubMedDate not supplied

Hydroxyurea inhibition of cellular and developmental activities in the decidualized and pregnant uteri of rats.

The cytotoxicity of hydroxyurea (HU), currently used to combat various cancers, sickle cell anemia and human immunodeficiency infection, was assessed by exposing decidualized and pregnant uteri of Sprague-Dawley rats to this drug. Consecutive daily doses of HU (500 mg/kg(-1)) for 4 days were injected subcutaneously during decidualization when proliferation of the deciduoma was biochemically analyzed on pseudopregnancy day 9, or injected intraperitoneally during pregnancy when uterine developmental processes were evaluated on gestation day 16. Hydroxyurea displayed prominent antiproliferative effects on decidual growth. These actions were comparable to significantly impaired (P<0.001) developmental responses (increases in post-implantation losses, in resorbed fetuses and in reduced fetal and placental weights) during pregnancy. The cellular components inhibited by HU were DNA, protein, nitric oxide synthase, a matrix metalloproteinase and decidual prolactin-related protein mRNA (P<0.05). Steroid-related endocrine events (serum progesterone concentrations, estrogen receptor and mRNA levels) were unaffected by HU, implying direct cellular action by the drug. Interestingly, endometrial alkaline phosphatase bioactivity was enhanced by HU (P<0.05). Subsequently, the reproductive toxicity of HU was apparently related to mitogenic and differentiation-induced endometrial cellular activities.

Animals↗

PubMed2002

Hydroxyurea treatment of sickle cell anemia in hospital-based practices.

In a published randomized clinical trial, hydroxyurea (HU) improved clinical outcomes in patients with sickle cell anemia (SCA). The mean treatment duration of that trial was 21 months. Here we attempt to determine whether the benefits associated with HU therapy of SCA have led also to successful patient acceptance of HU treatment in community practices, and whether successful clinical outcomes persist beyond 2 years. This is an observational retrospective chart study of the computerized medical records of 60 men and women with SCA who had HU treatment for at least 3 months and who were treated at teaching hospital subspecialty clinics in Baltimore, Maryland, and Washington, D.C. Thirty had remained on therapy for at least 24 months. Admissions declined in this group by 30% (P = 0.04). Declines were seen also in transfusion requirements (-58%, P = 0.07). In 17 of these 30 patients, at least 48 months of follow-up records were available. Fourteen of these remained on therapy the entire period, with similar and sustained reductions in admissions and transfusions. We conclude that hydroxyurea therapy of SCA applied in community settings leads to declining admissions and transfusion rates in many individuals for 4 years or more.

Adult↗