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PubMed1992

The interaction of 5-fluorouracil, hydroxyurea, and radiation in two human head and neck cancer cell lines.

We have investigated the effects of 5-fluorouracil (5-FU) and hydroxyurea (HU) with radiation on two human head and neck squamous carcinoma cell lines. SQ-20B has a D0 of 239 cGy and an S phase fraction of 37%, while SQ-38 has a D0 of 146 cGy and an S phase fraction of 31%. For SQ-20B the surviving fraction at 100 cGy was significantly reduced (p < 0.05) when cells were exposed to HU or to 5-FU or both chemotherapy agents together with radiation. No significant effect was seen for SQ-38 with either chemotherapy agent alone or in combination with radiation as compared with radiation alone. Therefore, additive cytotoxicity between 5-FU and HU and radiotherapy was observed only in a head and neck cancer cell line with a higher D0 and a higher S phase fraction.

Cell Survival↗

PubMed1978

Curing of an R factor from Escherichia coli by hydroxyurea and cytosine arabinoside.

Hydroxyurea (HU) and cytosine arabinoside (Ara-C) eliminate R factor R46 from Escherichia coli strain J5-3. The highest frequency of elimination for both drugs occurred at concentrations and times that produced the lowest survivor levels. 5% of cells were antibiotic-sensitive after 5 h incubation in 5 mg/ml Ara-C, whilst 6 and 7% of the survivors had lost the R factor after 8 and 24 h incubation, respectively in 20 mg/ml HU. The number of survivors began to increase after 5 h incubation in Ara-C, probably due to the inactivation of the drug in the phosphate-buffered medium. All four antibiotic resistances (ampicillin, streptomycin, sulphonamide and tetracycline) mediated by R46 were lost simultaneously and elimination of the whole plasmid was confirmed by conjugation experiments in which the 'cured' cells was shown to be as efficient recipients of R46 as the control R- strain in crosses with E. coli strain J6-2 (R46). No covalently closed circular plasmid DNA was demonstrable in cured cell lines. R+ and R- strains had similar sensitivities to HU but J5-3 R+ was much more sensitive to Ara-C than the isogenic R- strain. It may be concluded that HU eliminates R46 actively whereas although Ara-C may produce some active elimination it acts mainly by selection of R- cells present in the culture.

Culture Media↗

PubMed1978

Chronic granulocytic leukemia cutis treated with hydroxyurea. Report of a case.

The clinical course of a patient with chronic granulocytic leukemia cutis associated with myeloid metaplasia is described. Cutaneous manifestations of leukemia appeared only at the sites of bone marrow aspiration and vena puncture. Radiotherapy to both spleen and skin and chemotherapy with busulfan failed to control spreading cutaneous lesions. Treatment with hydroxyurea was followed by a marked reduction in spleen size, a decrease in white cell count and healing of the skin lesions.

Female↗

PubMed2002

Successful treatment for leg ulcers due to hydroxyurea in a patient with chronic myelogenous leukaemia.

A 51-year-old male who had intractable leg ulcers during treatment for chronic myelogenous leukaemia with hydroxyurea (HU) is reported. His leg ulcers were treated by application of tretinoin tocoferil (TT) ointment after surgical debridement; good results were obtained. Although stopping HU administration is vitally important, surgical debridement and TT application are effective for treating leg ulcers due to HU.

Antineoplastic Agents↗

PubMed1988

Concomitant hydroxyurea, 5-fluorouracil, and radiation therapy for recurrent head and neck cancer: early results.

We tested the combination of hydroxyurea (HU), 5-fluorouracil (5-FU), and concomitant radiotherapy (XRT) in a group of patients with advanced or recurrent head and neck cancer. Both drugs are effective single agents, have shown synergistic activity in vitro, and can act as radiation sensitizers. A 5-day course of radiotherapy, with simultaneous HU and continuous infusion 5-FU, was followed by a 9-day rest period; cycles were repeated until completion of XRT. Sixteen patients have completed their therapy. Eleven patients had recurrent disease after previous therapy with surgery (11 patients), radiotherapy (9 patients), and combination chemotherapy (4 patients). Five patients had not received previous local therapy. These patients had persistent disease after induction chemotherapy and/or were inoperable because of poor general medical condition. Of 15 patients evaluable for response, 9 had complete response, including 5 patients who had earlier local therapy; 5 had partial response; and 1 failed to respond. Toxicities included mild myelosuppression and mucositis. No unusual complication related to previous radiotherapy was observed. This regimen has shown impressive activity in a cohort of patients who are not usually responsive to other types of currently available therapy. We are continuing our investigation to further define efficacy, toxicity, and maximally tolerated doses of this regimen.

Aged↗

PubMed1983

5-Fluorouracil, vincristine and hydroxyurea combination chemotherapy in metastatic colorectal cancer.

Twenty consecutive patients who had biopsy proven metastatic colorectal cancer were treated with combination chemotherapy. The drug regimen (FVH), in a 4 week cycle, consisted of 5-fluorouracil (600 mg/m2 i.v. on days 1, 8, 15 and 22), vincristine (1.4 mg/m2 i.v. on day 4), and hydroxyurea (2400 mg/m2 p.o. on days 3, 10, 17 and 24). Three of the 18 evaluable patients achieved an objective tumor remission (2 CR and 1 PR) and 15 patients had stable disease. The overall response rate to FVH was therefore not superior to that achieved in patients who received 5-fluorouracil alone, and the overall survival in this study was comparable to that of other studies involving patients with metastatic colorectal cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1986

Augmentation of hydroxyurea cytotoxicity by sintamil in human chronic myeloid leukemia cells.

The in vitro effect of sintamil, as a modulator alone and in combination with hydroxyurea (HU), on cytotoxicity was studied in 16 cases of human chronic myeloid leukemia (CML). We investigated the cytotoxicity of the drugs as a function of the exposure dose (HU, 10(-4) M; sintamil, 10 micrograms/ml) and the exposure time (1 h) to the agent. Cytotoxicity was evaluated as the inhibition of incorporation of [3H-methyl]thymidine in the nucleic acids of CML cells. Cytotoxicity of HU was greatly enhanced (P less than 0.001) by 1 h exposure of the CML cells to sintamil. The present data indicate that sintamil potentiates the cytotoxic activity of HU in CML cells.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Short-term treatment with novel ribonucleotide reductase inhibitors Trimidox and Didox reverses late-stage murine retrovirus-induced lymphoproliferative disease with less bone marrow toxicity than hydroxyurea.

We evaluated the ability of a short course of treatment with the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) and two novel RR inhibitors Trimidox (TX) and Didox (DX) to influence late-stage murine retrovirus-induced lymphoproliferative disease. LPBM5 murine leukaemia virus retrovirus-infected mice were treated daily with HU, TX or DX for 4 weeks, beginning 9 weeks post-infection, after development of immunodeficiency and lymphoproliferative disease. Drug effects on disease progression were determined by evaluating spleen weight and histology. Effects on haematopoiesis were determined by measuring peripheral blood indices (white blood cells and haematocrit) and assay of femur cellularity and femoral and splenic content of colony-forming units granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). HU, TX and DX partially reversed late-stage retrovirus-induced disease, resulting in spleen weights significantly below pre-treatment values. Spleen histology was also improved by RR inhibitor treatment (DX>TX>HU). However, as expected, HU was significantly myelosuppressive, inducing a reduction in peripheral indices associated with depletion of femoral CFU-GM and BFU-E. In contrast, although TX and DX were moderately myelosuppressive, both drugs were significantly better tolerated than HU. In summary, short-term treatment in late-stage murine retroviral disease with HU, TX or DX induced dramatic reversal of disease pathophysiology. However, the novel RR inhibitors TX and DX had more effective activity and significantly less bone marrow toxicity than HU.

Animals↗

PubMed2003

Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia.

Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with beta-thalassemia intermedia. Effects in patients with beta-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent beta-thalassemia. The median follow-up was 19 +/- 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with beta-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited.

Adolescent↗

PubMed2005

The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells.

Hydroxyurea (HU), a drug effective in the treatment of sickle cell disease, is thought to indirectly promote fetal hemoglobin (Hb F) production by perturbing the maturation of erythroid precursors. The molecular mechanisms involved in HU-mediated regulation of gamma-globin expression are currently unclear. We identified an HU-induced small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR) protein, in adult erythroid cells using differential display. Stable SAR expression in K562 cells increased gamma-globin mRNA expression and resulted in macrocytosis. The cells appeared immature. SAR-mediated induction of gamma-globin also inhibited K562 cell growth by causing arrest in G1/S, apoptosis, and delay of maturation, cellular changes consistent with the previously known effects of HU on erythroid cells. SAR also enhanced both gamma- and beta-globin transcription in primary bone marrow CD34+ cells, with a greater effect on gamma-globin than on beta-globin. Although up-regulation of GATA-2 and p21 was observed both in SAR-expressing cells and HU-treated K562 cells, phosphatidylinositol 3 (PI3) kinase and phosphorylated ERK were inhibited specifically in SAR-expressing cells. These data reveal a novel role of SAR distinct from its previously known protein-trafficking function. We suggest that SAR may participate in both erythroid cell growth and gamma-globin production by regulating PI3 kinase/extracellular protein-related kinase (ERK) and GATA-2/p21-dependent signal transduction pathways.

Antigens, CD34↗

PubMed2004

Mortality in sickle cell patients on hydroxyurea therapy.

The efficacy of hydroxyurea (HU) and its role in the reduction in mortality in sickle cell patients has been established. Nevertheless, many patients still die of complications of this disease while on HU. Of the 226 patients treated with HU at our center, 38 died (34 of sickle cell-related causes). Acute chest syndrome (ACS) was the most common (35%) cause of death. Deceased and surviving patients did not differ significantly in average HU dose, baseline fetal hemoglobin (Hb F), or maximum Hb F response. However, the deceased patients were significantly older when HU was instituted, were more anemic, and more likely to have BAN or CAM haplotypes. They also had significantly higher serum blood-urea-nitrogen (BUN) and creatinine levels. Sickle cell patients who die while on HU therapy may represent a subgroup of older patients, possibly with more severe disease and more severe organ damage. Such patients need early identification and prompt HU institution.

Acute Disease↗

PubMed2004

Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience.

Hydroxyurea (HU) is considered to be the most successful drug therapy for severe sickle cell disease (SCD). Nevertheless, questions remain regarding its benefits in very young children and its role in the prevention of cerebrovascular events. There were 127 SCD patients treated with no attempt to reach maximal tolerated doses who entered the Belgian Registry: 109 for standard criteria and 18 who were at risk of stroke only. During 426 patient-years of follow-up for patients with standard criteria, 3.3 acute chest syndromes, 1.3 cerebrovascular events, and 1.1 osteonecrosis per 100 patient-years were observed. A subgroup of 32 patients followed for 6 years experienced significant benefit over this period. In each subgroup of children (younger than 2 years, 2-5, 6-9, and 10-19 years) followed for 2 years, clinical and biologic changes were similar, except for children younger than 2 years who had no total hemoglobin increase and remained at risk of severe anemia. In 72 patients evaluated by transcranial Doppler studies (TCD), 34 patients were at risk of primary stroke and only 1 had a cerebrovascular event after a follow-up of 96 patient-years. These results confirm the benefit of HU, even in very young children, and its possible role in primary stroke prevention.

Adolescent↗

PubMed2005

Nitric oxide generation from hydroxyurea: significance and implications for leukemogenesis in the management of myeloproliferative disorders.

The use of myelosuppressive agents to reduce the risk of thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET) has been associated with an increased risk of transformation to acute myeloid leukemia (AML). Whereas chlorambucil, busulfan, and radiophosphorus (32P) have been demonstrated to increase the risk of transformation, the leukemogenic potential of hydroxyurea (HU) continues to be a matter of debate. Clinical studies have suggested that HU may cause a small increase in the risk of AML, but it has proven difficult to establish whether AML is actually caused by HU or arises during the natural progression of PV and ET. Reports that HU undergoes metabolic activation to species that induce mutation appear to support the notion that it is leukemogenic. Here, we suggest that the ability of HU to induce mutation in cell culture studies results from the generation of nitrogen dioxide via the autoxidation of nitric oxide, a product of HU metabolism. However, we argue that autoxidation would not occur in vivo, leading to the conclusion that generation of the mutagen nitrogen dioxide is peculiar to cell culture systems and has little relevance to the use of HU in the management of PV and ET.

Cell Transformation, Neoplastic↗

PubMed2001

Five years of experience with hydroxyurea in children and young adults with sickle cell disease.

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P =.0002) and days in the hospital (P <.01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support. (Blood. 2001;97:3628-3632)

Acute Disease↗

PubMed2005

Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens.

BACKGROUND: Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy. METHODS: A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA < or = 400 copies/mL after > or = 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24). RESULTS: Baseline mean HIV-1 RNA was 3.86 log10 copies/mL and CD4+ cell count was 345 cells/mm3. A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (< 400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; < 50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm3 and -63 cells/mm3 (P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed. CONCLUSION: ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events.

Adult↗

PubMed2006

Hydroxyurea and sickle cell anemia: effect on quality of life.

BACKGROUND: The Multicenter Study of Hydroxyurea (HU) in Sickle Cell Anemia (MSH) previously showed that daily oral HU reduces painful sickle cell (SS) crises by 50% in patients with moderate to severe disease. The morbidity associated with this disease is known to have serious negative impact on the overall quality of life(QOL) of affected individuals. METHODS: The data in this report were collected from the 299 patients enrolled in the MSH. Health quality of llife (HQOL) measures were assessed in the MSH as a secondary endpoint to determine if the clinical benefit of HU could translate into a measurable benefit perceptible to the patients. HQOL was assessed with the Profile of Mood States, the Health Status Short Form 36 (SF-36), including 4-week pain recall, and the Ladder of Life, self-administered twice 2-weeks apart pre-treatment and every 6 months during the two-year, randomized, double-blind, treatment phase. The effects of factors including randomized treatment, age, gender, pre-treatment crises frequency, Hb-F level mean, daily pain from 4-week pre-treatment diaries, and 2-year Hb-F response level (low or high) were investigated. RESULTS: Over two years of treatment, the benefit of HU treatment on QOL, other than pain scales, was limited to those patients taking HU who maintained a high HbF response, compared to those with low HbF response or on placebo. These restricted benefits occurred in social function, pain recall and general health perception. Stratification according to average daily pain prior to treatment showed that responders to HU whose average daily pain score was 5-9 (substantial pain) achieved significant reduction in the tension scale compared to the placebo group and to non-responders. HU had no apparent effect on other QOL measures. CONCLUSION: Treatment of SS with HU improves some aspects of QOL in adult patients who already suffer from moderate-to-severe SS.

Activities of Daily Living↗

PubMed1987

Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin's lymphoma.

In experimental systems, hydroxyurea (HU) and cytarabine (ara-C) produce synergistic cytotoxicity to murine and human leukemia cells due to both cytokinetic and biochemical interactions that tend to enhance the effectiveness of ara-C. Therefore, we began a phase II trial of the combination of HU and ara-C to determine the efficacy and toxicity of this combination in treatment of patients with refractory non-Hodgkin's lymphoma. Chemotherapy began with HU 500 mg administered orally every six hours for four doses. Twelve hours following the fourth HU dose, ara-C 100 mg/m2/d was administered by continuous intravenous (IV) infusion for three days. Concomitantly with the three-day ara-C infusion, patients again received HU 500 mg orally every four hours. Cycles of therapy were repeated every 28 days. Twenty-five patients ranging in age from 26 to 70 years were enrolled in the study. Of 21 patients evaluable for response, nine (43%) obtained complete (CR) or partial remissions (PR). Most responding patients had either large-cell or cutaneous T cell lymphoma, and all but two had a performance status of 0 to 1 at entry in the study. The median survival for all responding patients was 13 months compared with 2.5 months for nonresponders. Patients obtaining a CR had a median survival of 27.5 months, and two of the four CRs remain alive and in remission at 10+ and 30+ months from achievement of CR status. The primary toxic effect of this regimen was bone marrow suppression. The median WBC nadir was 2,200 cells/microL, and the median platelet nadir was 80,000/microL. Other toxicities included mild nausea and vomiting and diffuse maculopapular rash. This biochemically rational approach to enhancing ara-C activity may have significant clinical utility and should be further explored in treatment of patients with large-cell and cutaneous T cell lymphomas.

Adult↗

PubMed1995

Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.

PURPOSE: A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS: The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION: High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.

Adolescent↗