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PubMed1991

Survival and analysis of failure following hydroxyurea, 5-fluorouracil and concomitant radiation therapy in poor prognosis head and neck cancer.

Thirty-nine patients with head and neck cancer were entered into Phase I-II study of simultaneous radiation therapy with continuous infusion fluorouracil at 800 mg/m2/day and escalating doses of hydroxyurea. Twenty of these patients had recurrent disease after previous surgery and/or radiation therapy (group 1). Nineteen patients had not received prior local therapy but had advanced-stage disease (group 2). Cycles were repeated every other week until the completion of radiation therapy. The median follow-up was 32 months. Patients with recurrent disease were generally treated with palliative doses of radiation (median dose 5,000 cGy) while previously untreated patients received radiation with curative intent (median dose 7,040 cGy). The response rate for 15 evaluable patients with recurrent disease was 93% with 40% of patients achieving a complete response. For 17 evaluable patients without recurrent disease the response rate was 100%, with a complete response rate of 71%. This regimen exhibited a high activity and significant palliative benefit in group 1 patients. However the local control rate was 25% (5/20) because the majority of patients in this group eventually developed a local recurrence. The local control rate for group 2 patients was 84% (16/19). The higher local failure rate in group 1 patients appeared to be attributable to the palliative doses of radiation delivered and the fewer cycles of treatment received. We conclude that this regimen has palliative benefit in patients who have failed prior local therapy and has the potential for cure in patients with poor prognosis advanced stage disease as well.

Adult↗

PubMed1991

A phase I study of a combination of allopurinol, 5-fluorouracil and leucovorin followed by hydroxyurea in patients with advanced gastrointestinal and breast cancer.

Twenty patients with advanced carcinomas of the colorectum, pancreas, stomach, and breast were enrolled in a Phase I study of a sequential administration of 5-fluorouracil-leucovorin (FU-LV) combination followed by hydroxyurea (HU) with allopurinol protection (HALF regimen). As a weekly regimen for 6 weeks, followed by a rest period of 2 weeks, FU was administered intravenously (i.v.) during infusion of a 2-hour i.v. infusion of LV at a dose of 500 mg/m2. Six hours following the FU-LV combination, HU (1 gm/m2) was administered orally. Allopurinol (300 mg every 8 hours, orally) was given the day before and on the day of the administration of the FU-LV combination. The starting dose of FU was 300 mg/m2, with escalations to 900 mg/m2. Mucositis, diarrhea, and hematologic toxicities were mild and sporadic with FU doses up to 750 mg/m2 and occurred in patients who had received prior treatment with FU and/or radiotherapy. Dose-limiting neurocerebellar toxicity was observed in 2 out of 6 patients who received a FU dose of 900 mg/m2. Three additional patients experienced moderate neuromotor toxicity at this dose level. Among 17 patients evaluable for response, partial responses were seen in 3 of the 9 patients with colorectal cancer, 1 of the 3 patients each with carcinoma of breast and pancreas. Three of the 5 responses occurred in patients who had received prior treatment with FU and/or radiation therapy. An FU dose of 750 mg/m2 is recommended for a Phase II trial of the HALF regimen.

Aged↗

PubMed1998

High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research.

Patients with histologically confirmed advanced colorectal cancer were randomized to receive folinic acid (FA; 500 mg/mq in 2-hour intravenous infusion) and 5-fluorouracil (5FU; 600 mg/mq given as an intravenous bolus 1 hour after FA), beginning every week for 6 weeks, followed by a 2-week rest period, either without hydroxyurea (HU, arm A) or with HU (35 mg/kg per day) given orally in three administrations (every 8 hours) starting 6 hours after 5FU administration (arm B). Six weekly doses were considered one course. One hundred eighty-two patients were randomized in this trial and 162 (89%) were evaluable for response: 81 patients in arm A and 81 patients in arm B. Objective response was observed in 18 (one complete response and 17 partial responses) of 81 evaluable patients (22%; 95% confidence interval, 13-31%) in arm A, and 24 (nine complete responses and 15 partial responses) of 81 patients (30%; 95% confidence interval, 20-40%) in arm B. There was no difference in terms of median time to progression and median survival. Gastrointestinal toxicity was the most frequently observed toxicity in both arms. The double modulation of 5FU, FA plus HU does not appear to be better than the classic 5FU plus FA schedule. This trial confirms that 5FU and FA reached a plateau of 20% to 30%.

Adenocarcinoma↗

PubMed1992

Hydroxyurea modulates 5-fluorouracil antineoplastic activity in advanced head and neck carcinoma pretreated with chemotherapy.

After informed consent 21 patients with advanced head and neck cancer resistant to folinic acid/5-fluorouracil (FA/5FU + cisplatin) were treated with weekly FA/5FU plus low dose hydroxyurea (HU) to evaluate if HU could further modulate 5FU antineoplastic activity. Five patients achieved a partial response (23.8%) which was short-lived (mean duration 6.5 months). Three patients (14%) had stable disease and 13 (62%) progressed. Among responders, four patients had epidermoidal carcinoma and one had clear cell carcinoma. Treatment was well tolerated and 5FU-related toxicity was not apparently worsened by the addition of HU. The most frequent toxicities were nausea/vomiting (81%), diarrhea (52%) and leukopenia (57%). Grade 3 nausea/vomiting and leukopenia were recorded in only 19 and 9% of cases, respectively. One patient had grade 1 cutaneous toxicity and a second patient showed a hand-foot syndrome. These results suggest that HU may further positively modulate 5FU antineoplastic activity.

Aged↗

PubMed1992

Hydroxyurea-induced cell death in human T lymphoma cells as related to imbalance in DNA/protein cycle and deoxyribonucleotide pools and DNA strand breaks.

The aim of this study was to elucidate the mechanism(s) behind the cellular toxicity of therapeutic concentrations of hydroxyurea (HU). Treatment of human T lymphoma cells (CCRF-CEM) with 60-100 microM of HU for 24 h decreased the growth rate by 90% due to accumulation of cells in early S phase. It induced a marked imbalance in both the DNA/protein cycle (as measured by two-parameter flow cytometry) and the deoxyribonucleotide (dNTP) pools. HU treatment did not enhance the frequency of DNA single-strand breaks (SSBs), as measured by the alkaline unwinding technique. Cell viability was unaffected. However, removal of HU led to 10-15% cell loss during the following 12 h period in parallel with increasing SSBs, and a rapid progression of cells through S and G2 stages. The unbalanced DNA to protein content per cell and the dNTP pools were normalized 6-12 and 24 h after removal of HU, respectively. These results show that marked changes in the DNA to protein ratio and dNTP pools alone are not directly lethal, but when combined with a high replicative DNA synthesis rate, as found after removal of HU, apparently lead to elevated cell death.

Cell Cycle↗

PubMed1994

Pharmacokinetics of hydroxyurea in nude mice.

Extrachromosomal DNA is the predominant form of gene amplification in human tumors. Hydroxyurea (HU) concentrations of 100-150 microM have been promising in vitro for extrachromosomal DNA elimination. The study objective was to determine the HU dose-concentration relationship in nude mice with HU doses from 0 to 200 mg/kg. For HU t1/2 determination, mice were injected with HU 100 mg/kg. A plasma concentration of 159 microM was achieved and a t1/2 of 11.3 min determined. Based on these findings, In vivo elimination studies will require frequent administration of HU to maintain plasma concentrations from 100 to 150 microM.

Animals↗

PubMed2000

Long-term hydroxyurea in combination with didanosine and stavudine for the treatment of HIV-1 infection. Swiss HIV Cohort Study.

OBJECTIVE AND METHODS: In 1998 we reported on a randomized comparison between stavudine plus didanosine plus placebo versus stavudine plus didanosine plus hydroxyurea (HU), in patients with a CD4 count of 200-500 x 10(6) cells/l. After 3 months, the HU group had a higher proportion of patients with viral load < 200 x 10 cells/l. At the end of the 3 months blinded period, patients in the placebo group had the option to add HU if their viral load remained > 200 x 10(6) cells/l. We report results after 24 months. RESULTS: Seventy-two patients were randomized to the HU arm, and a further 30 elected to add HU after 12 weeks. Twenty-four months after the start of the trial, only 25% of the 72 patients originally randomized to HU, and 20% of the 30 who added HU after week 12, were still taking it. The reasons for stopping HU were: lack of efficacy (45%), adverse events (37%) and patient or physician preference (18%). Side effects were more frequent in the didanosine/stavudine/HU group than in the didanosine/stavudine group: neuropathy (35 versus 15%, P< 0.02), fatigue (22 versus 7%, P< 0.01), and nausea or vomiting (26 versus 9%, P< 0.01). Of those who had discontinued HU, 73% were taking three drugs including a protease inhibitor. Patients who had started HU were compared with similar patients who had started protease inhibitors in the Swiss cohort. The probability of stopping HU was higher than the probability of stopping nelfinavir or indinavir, and similar to the probability of stopping ritonavir. CONCLUSION: HU increased the antiviral effect of stavudine plus didanosine. However, side effects were more frequent, and after 24 months the majority of patients had switched to protease inhibitor regimens.

Anti-HIV Agents↗

PubMed2001

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression.

BACKGROUND: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DESIGN: Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. METHODS: Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. RESULTS: Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. CONCLUSIONS: Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Adolescent↗

PubMed2004

Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects.

OBJECTIVE: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. METHODS: : HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add NVP and/or HU to the triple NRTI backbone of zidovudine plus lamivudine plus abacavir. Primary endpoint was treatment failure, defined as having plasma HIV RNA levels > 50 copies/ml after week 24, or discontinuation of randomized treatment. Follow-up was 72 weeks. RESULTS: For the 229 subjects, median plasma HIV-1 RNA was 4.61 log10 copies/ml and median CD4 cell count was 269 x 10 cells/l. NVP users reached plasma HIV-1 RNA < 50 copies/ml more rapidly than subjects using no NVP (log-rank test; P = 0.011). In the as-treated analysis, 21.6% of subjects using NVP versus 48.8% using no NVP reached the primary endpoint (P = 0.013). In the intent-to-treat analysis, 83.3% of subjects using HU versus 73.0% using no HU experienced treatment failure (P = 0.060), while no difference was observed in the as-treated analysis (34.5 versus 36.7%). Differences in the intent-to-treat analysis were accounted for by toxicity: 52.6% of subjects using HU experienced toxicity leading to discontinuation of randomized treatment versus 28.7% of subjects using no HU. CONCLUSION: The use of NVP in addition to a triple NRTI regimen improved both short- and long-term antiretroviral efficacy. The use of HU significantly contributed to treatment failure because of toxicity.

Adult↗

PubMed2005

Hydroxyurea exerts a cytostatic but not immunosuppressive effect on T lymphocytes.

OBJECTIVE: To demonstrate that, despite a dose-dependent cytostatic effect, hydroxyurea (HU) does not have immunosuppressive effects. METHODS: The effects of HU on T lymphocyte proliferation parameters, activation phenotype and cytokine production were examined in vitro after exposure to clinically relevant concentrations of HU (10, 50, and 100 micromol/l). The effects of HU in vivo on CD4 T cell counts, viral load, activation phenotype and virus-specific response were examined in 17 Rhesus macaques infected with SIV(mac251) and randomized into three groups: untreated controls; treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and didanosine (ddI) only; and treated with PMPA, didanosine, and HU. RESULTS: The in vitro inhibition of T lymphocyte proliferation confirmed the cytostatic effect of HU, with a linear dose-dependent effect; however, no relevant differences were found in the expression of activation markers between treated and untreated controls. Both T helper type 1 and type 2 cytokine production were enhanced by HU. Consistent with the in vitro results, a blunted increase of peripheral CD4 T cells was observed in vivo in the HU group, without relevant effects on the expression of activation markers, and SIV-specific T cell responses were not affected by HU. CONCLUSIONS: Hyper-proliferation of T-lymphocytes is a major factor contributing to HIV pathogenesis. HU exerts a cytostatic effect on T lymphocytes, without altering their activation and apparently without having an immunosuppressive effect. The increase in cytokine production at the single cell level might compensate for the decrease in the percentage of activated CD4 T lymphocytes, without overall impairment of HIV-specific immune responses.

Animals↗

PubMed1986

Altered patterns of organ distribution of autologous and grafted blood cells in mice treated with hydroxyurea.

Migration and distribution of lymphocytes and red blood cells were profoundly altered in C57BL/6 mice treated with the anti-mitotic drug hydroxyurea (HU). HU treatment given twice daily for four consecutive days, markedly reduced the population of nucleated cells in the spleen and bone marrow; the numbers of nucleated cells in spleen and bone marrow were reduced to 20% and 10% of normal values, respectively. Paradoxically, in the bone marrow of HU-treated mice, the numbers of mature erythrocytes were increased 8-fold, while in the spleen erythrocyte values were decreased. To explore this altered pattern of red blood cell partition, radiolabeled cells were injected and their migration traced in normal and HU-treated recipients. Both erythrocyte and leukocyte populations were observed to migrate preferentially to the bone marrow of HU-treated animals. The altered pattern of blood cell partition in the bone marrow could be explained by the induction of abnormal permeability of the bone marrow-blood barrier by the antimitotic drug. This point may be of importance when considering clinical bone marrow transplantation. It stresses the need for antimitotic treatment before grafting individuals with hemopoietic precursors.

Animals↗

PubMed2000

Long-term safety and antiretroviral activity of hydroxyurea and didanosine in HIV-infected patients.

Long-term safety, immunologic effects, and antiretroviral activity of hydroxyurea and didanosine were evaluated in this retrospective study. Some 65 HIV-1-infected patients (39 of whom were antiretroviral naive) were studied (mean baseline CD4 count, 362 cells/mm3; mean plasma HIV-1 RNA viral load, 4.8 log10 copies/ml). The mean treatment duration was 20 months. Overall tolerance was good: 15 patients interrupted treatment because of clinical or biologic side effects. Four patients experienced a category B event. Patients had a mean increase of 27 CD4 cell counts after 12 months, of 112 after 24 months and of 59 after 36 months. They had a mean 1. 03 log10 fall in HIV-1 RNA after 12 months, 1.59 log10 after 24 months, and 1.27 log10 after 36 months. After 12 months, 35% developed an HIV-1 RNA viral load <200 copies/ml, 53% after 24 months, and 36% after 36 months. Those whose viral load became undetectable after 12 months have significantly lower baseline RNA values (p =.03). Fourteen patients had a viral load <3.4 log10 copies/ml after 24 months of the double therapy. A prolonged viral load suppression can be achieved using a simple combination of two drugs that are inexpensive and well tolerated.

Adult↗

PubMedDate not supplied

Three-year follow-up of hydroxyurea treatment in severely ill children with sickle cell disease. The French Study Group on Sickle Cell Disease.

PURPOSE: To observe the safety and efficacy of hydroxyurea (HU), a drug that stimulates fetal hemoglobin (Hb F) production, in previously severely ill children with sickle cell disease. PATIENTS AND METHODS: HU was given in an uncontrolled study to 35 children with sickle cell disease, aged from 3 to 20 years, suffering from frequent painful crises. Mean duration of treatment was 32 months (range: 12-59 months). RESULTS: HU induced an increase in Hb F levels in all children out one; this increase was maximal after 9 months of treatment, was largely sustained thereafter, and was related to HU dose and inversely to patients' age. We also noted an apparent reduction in crisis, which occurred principally after 3 months of therapy and did not seem strictly correlated with the rise in Hb F level. No serious hematopoietic complication was observed. Growth curves and sexual development were not modified. CONCLUSION: Our data support the efficacy of HU in reducing painful events in children with sickle cell disease. Short- and middle-term tolerances are good. Thus, we think that HU can be given to children affected by frequent and severe painful crises. We recommend, however, very cautious use of this drug, because its long-term effects in children are still unknown.

Adolescent↗

PubMedDate not supplied

Sickle cell anemia with systemic lupus erythematosus: response to hydroxyurea therapy.

PURPOSE: To report the efficacy of hydroxyurea (HU) in a patient with sickle cell anemia (SCA) associated with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: An unusual association of SCA with SLE occurred in a 14-year-old black girl. Her medical history was significant for repeated vasoocclusive crises requiring repeated hospitalizations and transfusions, acute chest syndrome, hyperhemolytic crises, multiple transfusions resulting in iron overload, gall stones, avascular necrosis, and significant psychosocial problems. Her lupus activity was controlled with oral prednisone and hydroxychloroquine. Treatment with oral HU was instituted at an initial dose of 20 mg/kg with gradual increment to a maximum of 25 mg/kg daily. RESULTS: A dramatic clinical improvement was noted with HU therapy with no episode of pain crisis or hospitalization for 5 months. There was an increase in fetal hemoglobin (HbF) to 20.9% and mean corpuscular volume to 114.5 fl, but her Hb level remained steady at 7.5 g/dl. No toxicity was noted with HU therapy. In addition, a significant change was also observed in her school performance, social activities, and general quality of life. CONCLUSIONS: HU therapy may be beneficial and safe and should be considered for other patients who have SCA with SLE.

Adolescent↗

PubMedDate not supplied

Hydroxyurea therapy for pediatric patients with hemoglobin SC disease.

PURPOSE: Hydroxyurea (HU) has laboratory and clinical efficacy in hemoglobin SS (HbSS) disease, but its benefits in hemoglobin SC (HbSC) disease are unknown. A recent adult HbSC disease pilot trial with HU therapy documented a modest laboratory benefit. Our goal was to evaluate the laboratory and clinical responses of selected pediatric patients with severe HbSC disease to HU therapy. PATIENTS AND METHODS: As part of a retrospective case series, patients were selected from the Duke Pediatric Sickle Cell Program based on the frequency and severity of their vasoocclusive events or an episode of acute chest syndrome. Oral HU therapy was started as a single daily dose and increased to the maximally tolerated dose based on myelosuppression. Laboratory evaluation was performed at baseline and monthly thereafter. Once the maximum tolerated dose was reached, laboratory data were monitored bimonthly. RESULTS: We treated six severely affected pediatric HbSC patients with HU for a median of 27 months. Mean corpuscular volume increased significantly (+26 fL) without change in hemoglobin concentration (-0.1 g/dL); neutrophils decreased significantly. Percentage of fetal hemoglobin (+8.5%) and percentage of F cells (+35.7%) increased significantly. Two experienced only mild and reversible toxicity. CONCLUSION: The laboratory responses in our pediatric patients with HbSC disease were striking, with increases in percentage of fetal hemoglobin and percentage of F-cells approaching responses observed in adult and pediatric patients with HbSS disease. All patients improved clinically. Our findings demonstrate that HU therapy benefits pediatric patients with severe HbSC disease, although larger clinical trials of HU therapy in HbSC disease are warranted.

Acute Disease↗

PubMed2002

Use of hydroxyurea and recombinant erythropoietin in management of homozygous beta0 thalassemia.

This report describes the sustained response of an Iranian girl with homozygous beta(0) thalassemia (IVS-II-1G-->A) to hydroxyurea (HU) and recombinant erythropoietin (rEPO). Since the start of this regimen 7 years ago, she has been transfusion-independent and her hemoglobin is maintained between 9.5-11.0 gm/dL. She is maintaining consistent growth around the 10th percentile for age and enjoys a good quality of life. She has not had any therapy-related adverse effects. This experience suggests that therapy with HU and rEPO may be useful long-term in some patients with beta thalassemia.

Antisickling Agents↗

PubMed2003

Hydroxyurea and arginine therapy: impact on nitric oxide production in sickle cell disease.

PURPOSE: Recent data suggest that hydroxyurea (HU) increases the production of nitric oxide (NO), a potent vasodilator. NO is normally metabolized from l-Arginine (Arg). However, in vitro and animal experiments suggest that HU is the NO donor itself. In contrast, a recent study indicates that nitric oxide synthase (NOS) may play a role. Since adults with sickle cell disease (SCD) are Arg-deficient, Arg availability may limit the ability of HU to maximally impact NO production if an NOS mechanism is involved. The authors have previously shown that Arg supplementation alone induces a paradoxical decrease in NO metabolite (NO(x)) production. METHODS: The authors studied the effects of HU and Arg supplementation on NO(x) production. HU alone or HU + Arg was administered to patients with SCD at steady state, and sequential levels of Arg, serum NO(x) and exhaled NO were followed over 4 hours. RESULTS: After HU + Arg, all patients demonstrated a significant increase in serum NO(x) production within 2 hours. When the same patients were treated with HU alone (5.1 +/- 2 micromol/L), a mixed response occurred. NO(x) levels increased in four patients and decreased in one patient (-23.3 micromol/L). CONCLUSIONS: While Arg alone does not increase serum NO(x) production in SCD patients at steady state, it does when given together with HU. Hence, co-administration of Arg with HU may augment the NO(x) response in SCD and improve utilization of Arg in patients at steady state.

Adolescent↗

PubMed1999

Long-term hydroxyurea treatment in young sickle cell patients.

Hydroxyurea is the first drug that, under well-organized, large-scale trials in adults, has shown a beneficial effect on the clinical course of sickle cell disease. Several small-scale trials have been conducted in children, but they used different therapeutic schedules, and only one was a single-blind crossover trial. Still, children are clearly good responders to the treatment because a rapid clinical improvement was observed, with decreased frequencies of vaso-occlusive crises, acute chest syndromes, and transfusion requirements. Despite large interindividual variations, virtually all the children studied increased their fetal hemoglobin, mean corpuscular volume, and total hemoglobin. Follow-up varied from 6 months to 59 months. More than in adults, the fetal hemoglobin increase was sustained, and few side effects were observed. Large-scale, placebo-controlled studies seem no longer needed. Guidelines concerning patient selection, dosing schedules, and monitoring protocols as well as exhaustive registries for the detection of long-term side effects are necessary.

Adolescent↗