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PubMed1988

[Chemotherapy of chronic myelocytic leukemia. Status of the German Multicenter Study on busulfan versus hydroxyurea versus alpha interferon, October 1897].

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of 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 November 26, 1987, 321 CML-patients had been randomized, 147 for busulfan, 149 for hydroxyurea and 25 for interferon-alpha. The average age is about 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome-negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

Busulfan↗

PubMed2003

Pharmacokinetics of hydroxyurea in plasma and cerebrospinal fluid of HIV-1-infected patients.

Hydroxyurea has been shown to potentiate the activity of the antiretroviral nucleoside analogs. A significant complication of AIDS is invasion of the virus into the CNS, resulting in HIV-associated dementia (HAD). Because of the polar nature of these nucleosides and the presence of efflux pumps in the blood-brain barrier, only low CNS drug concentrations are achieved. Introduction of hydroxyurea into the CNS may therefore increase the antiviral activity of these drugs. This study evaluates the accessibility of hydroxyurea to the CNS following oral drug administration. Twelve HIV patients received 800 mg, 1000 mg, or 1200 mg oral hydroxyurea. Cerebrospinal fluid (CSF) and plasma drug concentrations were measured over 8 hours and simultaneously fitted to a pharmacokinetic model. It was determined that CSF hydroxyurea concentrations, corresponding to those found to increase antiretroviral nucleoside activity in vitro, were achieved.

AIDS Dementia Complex↗

PubMed2005

The influence of renal function on hydroxyurea pharmacokinetics in adults with sickle cell disease.

This was an open-label, nonrandomized, 2-center study conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea in adults with sickle cell disease (SCD). Seventeen patients were divided into 5 groups: normal renal function (n = 7), mild renal impairment (n = 2), moderate renal impairment (n = 3), severe renal impairment (n = 2), and end-stage renal disease (ESRD, n = 3). Except for patients with ESRD, all the patients received a 15-mg/kg single oral dose of hydroxyurea. Patients with ESRD received a 15-mg/kg oral dose of hydroxyurea on 2 occasions. Blood and urine samples were collected for the assessment of hydroxyurea pharmacokinetics. The results indicate that the systemic exposure increases and the urinary recovery decreases as the degree of renal insufficiency worsens. On the basis of the exposure and the apparent clearance from the current and 2 historical studies, the authors have proposed an initial dosing regimen of hydroxyurea (7.5 mg/kg/day) for SCD patients with CL(cr) <60 mL/min. This dosing strategy is anticipated to provide a safe dose for SCD patients with renal impairment.

Adult↗

PubMedDate not supplied

Hydroxyurea did not enhance the clinical response to vinblastine in patients with anthracycline-resistant metastatic breast cancer.

BACKGROUND: Vinblastine is commonly used in metastatic breast cancer after anthracycline failure. The response rate to vinblastine is approximately 20%, with short duration of response. In vitro studies have shown that the addition of hydroxyurea resulted in increased accumulation of vinblastine in tumor cells and in loss of double minutes. We evaluated the combination of vinblastine and hydroxyurea in patients with anthracycline-resistant metastatic breast cancer. PATIENTS AND METHODS: Fourteen assessable patients with metastatic breast cancer were entered in the study. All patients had progressed on anthracyclines or progressed within 8 months of stopping anthracyclines. Patients received hydroxyurea (500 mg orally) every Monday, Wednesday and Friday starting one week before the first course of chemotherapy and continuing throughout treatment until disease progression. Vinblastine (6 mg/m2) was given intravenously every 21 days, RESULTS: The median number of courses for vinblastine was 3.5 (range, 1-6). Three patients had partial responses in soft tissue metastases (21%). Four patients had stable disease. Four patients had > grade 2 neutropenia, and 1 patient had grade 4 thrombocytopenia. There were 2 cases of grade 3 constipation, 2 of grade 3 nausea, and 1 each of grade 2 neuropathy and myalgia. There was no treatment-related mortality. CONCLUSIONS: Low-dose hydroxyurea in combination with vinblastine has a 21% response rate in metastatic breast cancer after anthracycline failure. Toxicity was mild and generally reversible. At the adopted dose schedule of hydroxyurea, the antitumor activity of vinblastine in anthracycline-resistant metastatic breast cancer did not appear to be enhanced.

Adult↗

PubMed2004

Safety of hydroxyurea in the treatment of HIV infection.

Lifelong adherence to very complex anti-HIV therapy presents drawbacks such as drug resistance and chronic drug-related toxicity, underscoring the need for innovative therapeutic options. As it is becoming increasingly evident that immune activation may be responsible for immune pathology, novel approaches to limit immune activation are under investigation. Hydroxyurea is the prototype of a new family of anti-HIV drugs called virostatics, acting both as an antiviral (directly suppressing HIV) and cytostatic (preventing immune system overactivation). Data from in vitro and clinical studies have proven that hydroxyurea-based regimens are effective options for patients with HIV. However, concerns over hydroxyurea toxicity have limited its use. This review critically examines the role of hydroxyurea for HIV-infected patients, focusing on past and recent clinical trials including the RIGHT 702 study, which identified the safest and most efficacious hydroxyurea dose.

Anti-HIV Agents↗

PubMed2006

Acidification of the parasitophorous vacuole containing Toxoplasma gondii in the presence of hydroxyurea.

Toxoplasma gondii multiplies within parasitophorous vacuole that is not recognized by the primary no oxidative defense of host cells, mainly represented by the fusion with acidic organelles. Recent studies have already shown that hydroxyurea arrested the intracellular parasites leading to its destruction. In the present work we investigated the cellular mechanism involved in the destruction of intracellular Toxoplasma gondii. Fluorescent vital stains were used in order to observe possible acidification of parasitophorous vacuole-containing Toxoplasma gondii in presence of hydroxyurea. Vero cells infected with tachyzoites were treated with hydroxyurea for 12, 24 or 48 hours. Fluorescence, indicative of acidification, was observed in the parasitophorous vacuole when the cultures were incubated in presence of acridine orange. LysoTracker red was used in order to determine whether lysosomes were involved in the acidification process. An intense fluorescence was observed after 12 and 24 hours of incubation with hydroxyurea, achieving it is highly intensity after 48 hours of treatment. Ultrastructural cytochemistry for localization of the acid phosphatase lysosomal enzyme was realized. Treated infected cultures showed reaction product in vesicles fusing with vacuole or associated with intravacuolar parasites. These results suggest that fusion with lysosomes and acidification of parasitophorous vacuole leads to parasites destruction in the presence pf hydroxyurea.

Animals↗

PubMed1999

Hydroxyurea in two pregnant women with sickle cell anemia.

Hydroxyurea is classified as an S-phase antineoplastic agent (pregnancy category D). Two women became pregnant while taking hydroxyurea for sickle cell anemia and delivered live infants with no congenital anomalies. Although teratogenic effects of hydroxyurea were reported in animal studies, several case reports suggest the agent may have minimal teratogenic effects on the developing fetus. Fourteen cases of hydroxyurea therapy in pregnant patients with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease are reported in the literature. Three pregnancies were terminated by elective abortion; one woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. Further studies with larger numbers of patients receiving hydroxyurea during pregnancy, with longer follow-up of exposed children and more careful assessment of fetotoxic effects, are required before the agent can be promoted as safe in pregnancy.

Adult↗

PubMed1999

Hydroxyurea-induced fever in cervical carcinoma: case report and review of the literature.

This is a case presentation of a rarely seen hydroxyurea-induced fever in a patient with cervical adenocarcinoma receiving oral hydroxyurea given concurrently with external beam radiotherapy to the pelvis. In the fourth week of treatment, the patient developed recurrent febrile episodes, with no obvious etiology. Eventually, hydroxyurea was discontinued with no further recurrence of fever. A review of the medical literature on fever induced by hydroxyurea suggests a mechanism of delayed hypersensitivity. Since hydroxyurea is an often-used chemotherapeutic drug for various malignancies, clinical oncologists need to be aware of this unusual side effect. The diagnosis is by clinical exclusion and by the recurrent pattern of fever on rechallenge of the drug.

Adenocarcinoma↗

PubMed1999

Paclitaxel, 5-fluorouracil, hydroxyurea, and concomitant radiation therapy for poor-prognosis head and neck cancer.

A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose, </=75 Gy). Maximum tolerated doses of the two-drug combination of hydroxyurea and 5-FU were defined at 1 g given orally twice daily for a total of 11 doses and 800 mg/m2/d for 5 days (by continuous intravenous infusion), respectively. When cisplatin was added to this regimen, the observed myelosuppression necessitated the addition of granulocyte colony-stimulating factor. The recommended phase II doses for the three-drug combination were cisplatin 100 mg/m2 every 28 days, 5-FU 800 mg/m2/d for 5 days, and hydroxyurea 1 g orally twice daily for 11 doses. The feasibility of administering radiation at 1.5 Gy twice daily with chemotherapy was also established, which allowed the administration of 75 Gy over 5 cycles (10 weeks). The initial review of this trial suggested substantial toxicity, particularly mucositis and myelosuppression; however, local and regional control rates also were high. Most recently, paclitaxel has replaced cisplatin in this regimen. Recommended phase II doses were hydroxyurea 0.5 g orally twice daily for 11 doses, 5-FU 600 mg/m2/d for 5 days, and paclitaxel 20 mg/m2/d for 5 days, with radiation therapy administered twice daily in 1. 5-Gy fractions. A formal phase II study of this regimen in previously untreated patients with stage IV disease has recently completed accrual and is awaiting analysis. Evaluation of a simplified paclitaxel administration schedule (1-hour infusion on day 1 of chemoradiotherapy between the two radiation fractions) is under way. In addition, the feasibility of substituting gemcitabine for hydroxyurea is undergoing evaluation. Future trials in this disease should focus on developing new combinations that are less toxic and have similar efficacy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Hydroxyurea induces a senescence-like change of K562 human erythroleukemia cell.

Hydroxyurea, a differentiation-inducing agent of human erythroleukemia K562 cells, is commonly used to treat some types of leukemia. However, the mechanism for its therapeutic effect is not clearly understood yet. In this study, we have observed an interesting effect of hydroxyurea on tumor cells: an induction of senescence-like changes. Human erythroleukemia K562 cells, when treated with hydroxyurea for 7 days or more, underwent a change into phenotypically senescent cells together with a reduction of hemoglobin generation, a differentiation marker. The hydroxyurea-treated cells showed positive senescence associated-beta-galactosidase staining, a senescence index, and the accumulation of cdk (cyclin dependent kinase) inhibitors, such as p16INK4a, p21Waf1, and p27Kip1, implicated in cellular senescence. Nonetheless, these changes were not accompanied by DNA fragmentation. Taken together, we summarize that the long-term treatment of cancer cells with hydroxyurea can induce cellular senescence different from differentiation or programmed cell death.

Antineoplastic Agents↗

PubMedDate not supplied

The effects of lithium in reversing hydroxyurea induced suppression of hematopoietic progenitor cells in vitro using retroviral infected long-term marrow cultures.

Lithium has been known for its ability to induce the production of hematopoietic cells following administration in vivo to minimize the toxic effects on hematopoiesis as a consequence of drug treatment. The drug hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been used in the treatment of a variety of neoplastic and non-neoplastic diseases, such as cancer and sickle cell anaemia. Hydroxyurea has more recently been implicated for use in the treatment of acquired immunodeficiency syndrome (AIDS). However, its major limitations have been due to its toxicity. Hydroxyurea selectively inhibits DNA synthesis and due to its brief duration, the drug is only toxic to those cells which are selectively synthesizing DNA during the period of exposure. The most important of these toxicities, and which serves as a dose limiting factor in treatment, is the induction of bone marrow suppression. In this study we investigated the possible beneficial effects of administering lithium (LiCl) to murine leukemia virus (MuLV) infected and non-infected long term bone marrow cultures (LTBMC). These cultures were then treated with either 0.2 mM hydroxyurea, 1.0 mM LiCl, or a combination of both. Samples were collected from LTBMC supernatants at 1, 2, 3, 4, 5 and 6 weeks post-treatment. Culture supernatants were then monitored to observe their repopulation of hematopoietic progenitors. The results demonstrated the effects of lithium in restoring hydroxyurea suppressed numbers of myeloid (CFU-GM) progenitors to within a normal range and also in re-establishing erythroid (BFU-E) progenitors.

Animals↗

PubMed2001

Leukemic transformation of polycythemia vera after treatment with hydroxyurea with abnormalities of chromosome 17.

The leukemogenic risk attributed to therapy of polycythemia vera with radiophosphorus and alkylating drugs has led, over the last 20 years, to the increased use of myelosupressive nonmutagenic drugs, especially hydroxyurea. But there exist reports, which showed the development of polycythemia vera into acute leukemia not only in patients treated with alkylating agents and radiophosphorus but also with single hydroxyurea. In this article we present two cases of polycythemia vera, in which the development to acute myeloblastic leukemia occurred after long-term treatment with hydroxyurea. Significant is the fact, that in both presented cases cytogenetic and FISH analysis showed abnormalities of chromosome 17, in the one of case fullfilled criteria for "17p-syndrome". Due to the possibility of leukemogenic potential in the time of hydroxyurea treatment, it is necessary to be careful especially in young patients. The dynamic follow up of cytogenetic analysis is necessary, especially, in those, where long-term hydroxyurea therapy is supposed.

Antineoplastic Agents↗

PubMed1999

[Analysis of the binding of GATA factors to the regulatory elements of human beta-globin gene in hydroxyurea-induced and uninduced HEL cells].

HEL cells, a human erythroleukemia cell line, expressing mainly the gamma-globin genes, small amount of epsilon-globin gene, but not beta-globin gene. Our previous studies demonstrated that beta-globin gene could be expressed in HEL cells induced by hydroxyurea. However, the molecular mechenism is still unknown. Here the binding patterns of GATA factors (GATA-1 and GATA-2) to the regulatory elements of human beta-globin gene were examined with the nuclear extracts from hydroxyurea-induced and uninduced HEL cells. Our results showed in EMSA assay that GATA factors could bind to the core sequence of HS2(-10681 to -10971 bp), the 3' flanking sequence of HS2 core(-10323 to -10680 bp) and the promoter of human beta-globin gene(+20 to -112 bp). However, the binding patterns between hydroxyurea-induced and uninduced HEL cells were different. Furthermore, by using Western-blot analysis, our data showed that the amount of GATA-2 was decreased in hydroxyurea-induced HEL cells. In contrast to GATA-2, the amount of GATA-1 was increased in hydroxyurea-induced HEL cells. These results showed that the different members of GATA family might play different roles during the differentiation of erythrocytes. GATA-1 may stimulate the differentiation of HEL cells, while GATA-2 can probably inhibit the differentiation of HEL cells.

Cell Differentiation↗

PubMed2003

Reversible leg ulcer due to hydroxyurea in a case of chronic myeloid leukemia.

The cutaneous side effects of hydroxyurea are lesser known complication of long term hydroxyurea therapy in myeloproliferative disorders. We report a non-diabetic patient, who developed hydroxyurea dermopathy (leg ulcers) during long-term treatment with hydroxyurea for chronic myeloid leukemia (CML). The time course of the development of ulcers and its healing suggests that these resulted from the direct toxicity of hydroxyurea. We aim to increase clinical awareness of this problem.

Adult↗

PubMed2004

Effect of hydroxyurea and etoposide on transduction of human bone marrow mesenchymal stem and progenitor cell by adeno-associated virus vectors.

AIM: To study the effect of hydroxyurea and etoposide on transduction of human marrow mesenchymal and progenitor stem cells by adeno-associated virus (AAV). METHODS: Isolated human bone marrow mesenchymal stem and progenitor cells (hMSCs) were cultured in DMEM containing 10% FBS or 5% FBS and dexamethasone 1 micromol/L respectively. After being treated with hydroxyurea and etoposide, hMSCs were transduced by AAV-LUC. After two days luciferase activity (relative light unites per second or RLU/s) were tested, which indirectly reflected the relative transduction efficiency of different groups, and virus DNA was isolated by Hirt extraction for Southern hybridization. RESULTS: Transduction luciferase activity and transduction efficiency in cultures treated with hydroxyurea and etoposide were significantly higher than that in control cultures. Dividing cells had about 20-fold higher transduction efficiency compared with control cells. Transduction efficiency in stationary cells was about 50 times higher than that in control cells. Southern analysis showed that hydroxyurea and etoposide enhanced second-strand DNA synthesis by rAAV. CONCLUSION: Hydroxyurea and etoposide could increase transduction efficiency of hMSCs by AAV vectors, and stationary cells were more sensitive to these drugs than dividing cells.

Bone Marrow Cells↗

PubMed2005

[Evaluation of clinical response by hydroxyurea in 132 patients with major sickle cell anemia].

Hydroxyurea is used since close to 10 years in the treatment of major sickle cell anemia. In African sub Sahara, very little study have been dedicated. Yet, this drug represents nowadays, an alternative tot the bone marrow transplantation in the treatment of this illness. This study permits to illustrate the beneficial effects of this drung on 132 patients affected by of major sickle cell anemia. It is about patients whose middle age is of 28 years (range 14 and 54 years), most frequently masculine sex, followed regularly in the service of haematology of CHUB. The treatment consisted to the administration of the hydroxyurea to the posology between 10 and 30 mg/kg per day. The essentially clinical assessment focused on the sickle cell anemia crises and the modifications of hematologic's parameters. The experimentation has been pursued beyond the 18th month among 108 patients. It takes out again of this survey disappearances of the vasculo occlusive crises among 103 patients on 132 (78.03%) during the first 18 months of the survey. Only 10 patients (7.57%) benefited blood transfusion during the period of the survey because of the infectious complications. The hydroxyurea led a meaningful and spontaneous increase of the haemoglobin rate (+2,54 g/dl) of the middle globular volume (+ 16,02 femtolitres) as well as of the rate of haemoglobin foetale on 65 estimated patients. The hydroxyurea didn't bring any objective improvement on the pre-existing dénénératives complications. The treatment has been interrupted precociously among 5 patients for cytopenia. This survey confirms to short and middle term the beneficial effects of the hydroxyurea on the major sickle cell anaemia.

Adolescent↗

PubMed1992

Escherichia coli ribonucleotide reductase. Radical susceptibility to hydroxyurea is dependent on the regulatory state of the enzyme.

Ribonucleotide reductase catalyzes the reduction of ribonucleotides to their corresponding deoxyribonucleotides via a radical-mediated mechanism. The enzyme from Escherichia coli consists of the two non-identical proteins, R1 and R2, the latter of which contains the necessary free radical located to a tyrosine residue. The radical scavenger hydroxyurea was found to reduce the tyrosyl radical of R2 in a second-order reaction. The rate constant (0.50 M-1 s-1 at 25 degrees C) for this process was several orders of magnitude lower than the hydroxyurea-dependent reduction of free tyrosyl radicals in solution. This difference probably reflects the fact that the R2 tyrosyl radical is buried in the interior of the protein. Formation of the R1R2 complex changed the susceptibility of the radical to hydroxyurea in a manner that reflects the regulatory state of the holoenzyme. Furthermore, binding of substrate or product to the holoenzyme complex made the R2 radical at least 10 times more susceptible to inactivation by hydroxyurea than it was in the isolated R2 protein. One active site mutation in the R1 protein was shown to affect the sensitivity of the tyrosyl radical of R2 differently than wild type protein R1 does. Our results clearly show that the susceptibility of the tyrosyl radical in R2 to inactivation by hydroxyurea can be used as an efficient probe for the regulatory state of the holoenzyme complex.

Escherichia coli↗

PubMed1992

Cytotoxic synergy of cisplatin with concurrent hydroxyurea and cytarabine: summary of an in vitro model and initial clinical pilot experience.

Cytarabine and hydroxyurea in combination are known to inhibit the DNA excision repair system. Given this system is responsible for repair of cisplatin-DNA adducts, we hypothesized that combining cytarabine, hydroxyurea, and cisplatin in an appropriate schedule might inhibit adduct repair, increase the number of DNA lesions, and produce synergistic cell kill. In vitro experiments using clinically achievable doses and schedules of these antimetabolites demonstrated cytotoxic synergy with the three-drug combination, but little or no such synergy with either antimetabolite plus cisplatin. The inclusion of hydroxyurea was necessary to achieve maximum synergy. Increased levels and persistence of cisplatin-induced DNA interstrand cross-links were observed, suggesting repair inhibition may have occurred. The dose of cisplatin required to inhibit colony formation by 90% was reduced approximately one third, even after normalization for the cytotoxic component(s) of hydroxyurea, cytarabine, and hydroxyurea plus cytarabine. Using one of the two optimal in vitro schedules for the three-drug combination, we performed a clinical pilot study in two patient cohorts (with and without prior systemic therapy). Administration of the program was feasible, and resulted in dose-limiting thrombocytopenia only in the cohort with prior chemotherapy. Azotemia was treatment-limiting in responding patients. Responses were observed in patients with a variety of solid tumors, including several patients who had previously failed cisplatin therapy. Modifications of this program are discussed, which have, to date, significantly decreased the toxicity concerns raised by the first trial. Phase II trials are planned in patients with a variety of cisplatin-responsive and nonresponsive neoplasms.

Administration, Oral↗