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At least 19 recordsLinked to original sources
PubMed2003

Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

Adolescent↗
PubMed1997

Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine.

The in vitro and in vivo antiviral activity of hydroxyurea in combination with either zidovudine or didanosine was evaluated in primary human peripheral mononuclear cells and in a cohort of 29 asymptomatic patients infected with HIV. In vitro, hydroxyurea alone did not significantly affect HIV replication, whereas the combination of hydroxyurea with didanosine was more effective than the combination of hydroxyurea with zidovudine. Our clinical results confirmed these studies. Patients were randomly assigned to five arms (zidovudine, hydroxyurea or didanosine monotherapy, or hydroxyurea in combination with either zidovudine or didanosine) to evaluate preliminary safety and efficacy. Bone-marrow toxicity occurred in two patients treated with zidovudine plus hydroxyurea, alopecia was reported in one patient treated with hydroxyurea monotherapy, and there were no toxic effects recorded in the remaining three groups. Plasma viraemia was not influenced by hydroxyurea monotherapy, and the hydroxyurea-zidovudine combination did not give any advantage over either zidovudine or didanosine monotherapy (0.3-0.5 log decrease in plasma viraemia). In contrast, a 1.1 log drop in plasma viraemia was observed in patients treated with hydroxyurea plus didanosine, this reduction was sustained throughout the 24-week course of the treatment. Combination therapy with hydroxyurea and didanosine exhibited statistically significant improvements compared with the other therapeutic approaches. Although further clinical trials are required, these results suggest that hydroxyurea in combination with didanosine might be an effective and well-tolerated, simple and affordable, treatment for HIV infection.

Adult↗
PubMed2000

Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $-340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $-610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater.

Adult↗
PubMed1995

Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

BACKGROUND: In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. METHODS: In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. RESULTS: Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS: Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

Adult↗
PubMed1997

Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea.

In this paper the authors present the first evidence that meningiomas respond to treatment with hydroxyurea. Hydroxyurea was administered as an adjunct chemotherapeutic treatment in patients with recurrent and unresectable meningiomas. Hydroxyurea was used because experimental data demonstrated that it inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis. The authors therefore treated four selected patients with hydroxyurea. All patients had undergone multiple gross resections and all except one received radiotherapy. Three patients with recurrent Grade I meningiomas assessed according to World Health Organization (WHO) guidelines received hydroxyurea because of an increased tumor growth rate, documented by magnetic resonance (MR) imaging, within a 6- or 12-month interval. A fourth patient with a malignant meningioma (WHO Grade III) began a course of treatment with hydroxyurea immediately after his sixth palliative operation without waiting for another relapse to be demonstrated on MR imaging. Because of their location and invasive growth behavior none of the meningiomas could have been removed completely by surgical intervention. All patients received hydroxyurea at a dosage level of 1000 to 1500 mg/day (approximately 20 mg/kg/day). In a man with a large sphenoid wing meningioma invading the right cavernous sinus and the temporal base, the intracranial tumor mass was reduced by 60% during 6 months of treatment. A woman with a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus exhibited a 74% decrease of the initial tumor volume in 10 months of treatment with oral hydroxyurea. Serial MR images obtained monthly revealed that the process of size reduction was continuous and proportionate. The shrinkage of the tumor was accompanied by a complete remission of symptomatic trigeminal neuralgia after 2 months and by improved abducent paresis after 5 months. The third patient had a slowly growing meningioma that exhibited a 15% reduction in mass when reassessed after 5 months of hydroxyurea treatment. The fourth patient with the malignant meningioma in the left cerebellopontine angle has had no recurrence for 24 months. Long-term treatment with hydroxyurea may result in full remission of tumors in meningioma patients. The preliminary data indicate that hydroxyurea provides true medical treatment in patients with unresectable and recurrent meningiomas, replacing palliative surgery and radiotherapy in the management of this disease.

Adult↗
PubMed1997

Nitric oxide generation from hydroxyurea via copper-catalyzed peroxidation and implications for pharmacological actions of hydroxyurea.

We investigated the generation of nitric oxide (NO) by H2O2-dependent peroxidation of hydroxyurea in the presence of copper-containing proteins such as Cu,Zn-superoxide dismutase (Cu,Zn-SOD) or ceruloplasmin as a catalyst. In the reaction mixture of hydroxyurea, CuZn-SOD, and H2O2, NO generation was identified by measuring the specific electron spin resonance (ESR) signal of 2-phenyl-4, 4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO). The ESR signal of the NO-hemoglobin adduct was also detected in human red blood cells during copper-catalyzed peroxidation of hydroxyurea. The NO production during peroxidation of hydroxyurea was quantified as NO2- formation, measured by using the Griess assay, the amount of NO2- was dependent on the concentrating of hydroxyurea of the reaction mixture. ESR spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) showed hydroxy radical (OH) generation in the reaction of H2O2 with either Cu,Zn-SOD or ceruloplasmin. Several OH scavengers, such as ethanol, thiourea, DMPO, and dimethylsulfoxide, and the metalchelating agent diethylenetriaminepentaacetic acid significantly inhibited NO generation from hydroxyurea. This indicates that NO release from hydroxyurea may be mediated by OH derived from the copper-catalyzed Fenton-like reaction. Incubation of hydroxyurea and Cu,Zn-SOD with xanthine oxidase and hypoxanthine in a system forming O2- -->H2O2 also resulted in appreciable NO production. These results suggest that NO production from hydroxyurea catalyzed by copper-containing proteins may be the molecular basis of the pharmacological and antitumor action of hydroxyurea.

Ceruloplasmin↗
PubMed1993

Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group.

In a randomized multicenter study the influence of hydroxyurea versus busulfan on the duration of the chronic phase and on survival of chronic myelogenous leukemia (CML) was determined. In addition cross resistance and adverse reactions of the drugs were analyzed. From July 1983 to January 1991, 441 CML patients were randomized to receive hydroxyurea or busulfan. Of these, 90.7% were Philadelphia positive; 25.7% were low, 38.2% intermediate, and 36.2% high risk patients according to Sokal's score. The median survival of the busulfan treated Philadelphia-positive patients is 45.4 months and of the hydroxyurea group 58.2 months (P = .008). The survival advantage for the hydroxyurea treated patients is recognized in all risk groups. Sixty four patients reached therapy resistance before blast crisis and were crossed over to the alternative drug. The 23 patients with primary hydroxyurea had a median survival of 5.6 years, the 41 patients with primary busulfan therapy a median survival of 2.7 years (P = .02). Adverse reactions were less frequent with hydroxyurea with no severe adverse effects (lung fibrosis, long lasting bone marrow aplasia). The analysis of white blood cell counts in the course of treatment showed lower counts in the hydroxyurea patients. We conclude that hydroxyurea is superior to busulfan in therapy of CML in chronic phase and should be used as first line therapy. Busulfan may have a role as secondary therapy after hydroxyurea resistance or intolerance.

Blast Crisis↗
PubMed2003

Hydroxyurea analogues as kinetic and mechanistic probes of the nitric oxide producing reactions of hydroxyurea and oxyhemoglobin.

Derivatives of N-hydroxyurea that contain an N-hydroxy group react with oxyhemoglobin to form methemoglobin and variable amounts of nitrite/nitrate. Compounds with an unsubstituted -NHOH group produce the most nitrite/nitrate, which provides evidence for nitric oxide formation. The rate of reaction of these N-hydroxyurea derivatives with oxyhemoglobin correlates well with that compound's oxidation potential. Aromatic N-hydroxyureas react 25-80-fold faster with oxyhemoglobin than with N-hydroxyurea, suggesting other N-hydroxyurea analogues may be superior nitric oxide donors. Electron paramagnetic resonance spectroscopy shows that the formation of a low-spin methemoglobin-hydroxyurea complex is critical for iron nitrosyl hemoglobin formation. These results show that iron nitrosyl hemoglobin formation from the reaction of hydroxyureas and hemoglobin requires an unsubstituted -NHOH group and that the nitrogen atom of the non-N-hydroxy group must contain at least a single hydrogen atom. These results should guide the development of new hydroxyurea-based nitric oxide donors and sickle cell disease therapies.

Electrochemistry↗
PubMed1988

Induction of achromosomal cleavage by hydroxyurea in starfish embryo and the reversal by a combination of deoxyadenosine and deoxycytidine: possible involvement of salvage pathway for deoxynucleoside triphosphate biosynthesis in the presence of hydroxyurea.

Effects of hydroxyurea, an inhibitor of ribonucleotide reductase, on cleavage of starfish embryos were studied. In the presence of 1 mM hydroxyurea, fertilized eggs of the starfish, Asterina pectinifera, cleaved up to the 256-cell stage and decomposed before blastulation. Before the 16-cell stage, each blastomere contained a normal nucleus or chromosomes with mitotic apparatus. The cleavage after the 16-cell stage was slow compared to the control embryos, and not all blastomeres contained a nucleus or normal chromosomes. During the fifth cell division (between 16-cell- and 32-cell-stage embryos), chromatin mass unassociated with the mitotic apparatus remained near the cleavage furrow. When hydroxyurea was removed before the 16-cell stage, the embryos developed to normal bipinnalia larvae via normal blastulae. However, the embryos were disintegrated before blastulation when hydroxyurea was removed after the 32-cell stage. DNA synthesis was normally observed before the 16-cell stage but not after the 16-cell stage, but dNTP contents in the embryos remained low throughout development in the presence of hydroxyurea. The achromosomal cleavage observed in the presence of hydroxyurea was reversed by the combination of extracellular dAR and dCR. Therefore, it is assumed that the synthesis of dNTPs required for DNA synthesis in the presence of hydroxyurea occurs via the salvage pathway using deoxynucleosides (dNR) (dNR to dNTP via dNMP and dNDP).

Animals↗
PubMed1997

Hydroxyurea dermopathy: a unique lichenoid eruption complicating long-term therapy with hydroxyurea.

BACKGROUND: Hydroxyurea is usually a well tolerated antitumor agent. OBJECTIVE: Our purpose was to describe a distinct clinical and histologic eruption in patients receiving long-term hydroxyurea therapy. METHODS: The clinical, histologic, and immunopathologic features of six patients with hydroxyurea dermopathy are described. RESULTS: Three women and three men were identified. The average age was 61 years. Hydroxyurea had been used for an average of 5 years. Lichenoid papules, telangiectasia, and poikilodermatous lesions on the dorsal hands and digits were the most common findings. Interface dermatitis, focal lichenoid reaction with epidermal atrophy, and Civatte bodies were the most common histologic findings. Endothelial swelling also was noted. Cytoid staining with multiple conjugates was the most common immunopathologic finding. Four patients showed significant improvement after discontinuation of hydroxyurea. CONCLUSION: A distinct cutaneous reaction to long-term administration of hydroxyurea has been characterized. Cessation of treatment is necessary for healing or improvement. We have designated this eruption hydroxyurea dermopathy.

Aged↗
PubMed1995

Design of the multicenter study of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia is a randomized double-blind placebo-controlled trial to test whether hydroxyurea can reduce the rate of painful crises in adult patients who have at least three painful crises per year. The sample size of 299 patients yields at least 90% power to detect a 50% or greater reduction in crisis rate. Dosage starts at 15 mg/kg/day and is titrated to the patient's maximum tolerated dose up to 35 mg/kg/day. Placebo dosage is titrated in similar fashion to maintain blinding. Attempts are made to ascertain medical contacts for at least 2 years after study entry. The Core Laboratory, Treatment Distribution Center, and Data Coordinating Center collaborate to provide standardized monitoring for toxicity and dose adjustments. The Core Laboratory also reduces the possibility of inadvertent unmasking of treatment assignment during review of hematologic data in clinical centers. An independent Crisis Review Committee classifies clinical events to assure that outcome evaluations are standardized and unbiased by knowledge of treatment assignments. The Data and Safety Monitoring Board assures scientific integrity of the study, as well as the safety and ethical treatment of study patients. We expect the study to determine whether or not treatment with hydroxyurea can offer significant clinical benefit to patients with the most common hereditary disorder among African-Americans in the United States.

Adult↗
PubMed1967

Studies with hydroxyurea. VII. Hydroxyurea and the synthesis of functional proteins.

Hydroxyurea affected neither the synthesis nor the degradation of bacterial messenger-ribonucleic acid. The proteins made by hydroxyurea-treated cells were structurally intact and fully functional. Since the expression of the lethal action of hydroxyurea requires active protein production, the data indicate that treated cells do not die as the result of the synthesis of abnormal proteins.

Alkaline Phosphatase↗
PubMed1996

Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group.

It is the long-term goal of the German CML Study Group and of the Süddeutsche Hämoblastosegruppe (SHG) to improve survival of patients with chronic myelogenous leukemia (CML). In a first randomized study (CML Study I) monotherapies with hydroxyurea or interferon alpha (IFN-alpha) were compared with a standard busulfan regimen with regard to duration of the chronic phase and survival. The main results of this study were published, 1-3 and a long-term follow up is planned. In a second randomized study the effect of the combination of IFN-alpha and hydroxyurea versus hydroxyurea monotherapy on survival is being investigated. This paper provides a first preliminary report on the study concept, patient recruitment, state of documentation and initial patients' characteristics 9 months after closure of the study.

Adult↗
PubMed1966

Studies with hydroxyurea. II. Prolonged exposure of Escherichia coli to hydroxyurea.

Rosenkranz, Herbert S. (Columbia University, New York, N.Y.), and Howard S. Carr. Studies with hydroxyurea. II. Prolonged exposure of Escherichia coli to hydroxyurea. J. Bacteriol. 92:178-185. 1966.-Concurrent with an inhibition of the synthesis of deoxyribonucleic acid, hydroxyurea devitalized Escherichia coli when exposure to the drug was prolonged to more than 3 hr. Active protein synthesis, but not ribonucleic acid (RNA) production, was a prerequisite for this lethal action. These findings are contrasted to thymineless death, which requires RNA synthesis.

Antimetabolites↗
PubMed1998

Randomized study on hydroxyurea alone versus hydroxyurea combined with low-dose interferon-alpha 2b for chronic myeloid leukemia. The Benelux CML Study Group.

Interferon-alpha (IFN-alpha) is considered the standard therapy for chronic myeloid leukemia (CML) patients not suitable for allogeneic stem cell transplantation. From 1987 through 1992, 195 patients in the Benelux with recent untreated CML were randomized between low-dose IFN-alpha2b (3 MIU, 5 days/wk) or hydroxyurea alone (control group). The white blood cell count had to be kept less than 10 x 10(9)/L in both arms; to this end, the IFN group received additional hydroxyurea, if necessary. The complete hematologic responses at 6 months in the IFN group were 62%, versus 38% in the control group. In the IFN group, a complete hematologic response at 6 months predicted a better survival (P = .001), but such a tendency was also seen in the control group (P = .07). Cytogenetic responses in the IFN group yielded 9% complete responders, 7% partial responders (<35% Ph+), and 24% minor responders (36% to 95% Ph+). The quality of cytogenetic response within the first 24 months was highly predictive for survival (P = .002). Twenty-four patients discontinued IFN-alpha because of side effects, but they did this at a long median interval of 17.6 months; the remaining patients did not require dose adaptations. Although the hematologic and cytogenetic responses in the IFN group were higher than in the control group, the duration of chronic phase from randomization was not statistically different with 53 and 44 months in the IFN and control group, respectively. Also, no advantage for survival calculated from diagnosis was seen for the IFN group (median, 64 months) compared with the control group (median, 68 months).

Adult↗
PubMed2003

Acute leukemia and myelodysplasia in patients with a Philadelphia chromosome negative chronic myeloproliferative disorder treated with hydroxyurea alone or with hydroxyurea after busulphan.

Eighty-three patients with various chronic myeloproliferative disorders [polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myelofibrosis (IMF)] were analyzed for the occurrence of acute myeloid leukemia (AML) and myelodysplasia (MDS) during treatment with hydroxyurea (HU) alone or HU following treatment with busulphan (BU). A total of 58 patients (29 PV, 14 ET, 12 IMF, 3 unclassified) had been treated with HU. Thirty-five of these patients had been treated with HU alone whereas 18 patients had received both HU and BU. The follow-up period was 7.8 years. Twenty-five patients had not been treated with HU. In this patient group, 4 patients had been treated with BU. The follow-up period was 10.5 years. In the HU-treated group (n = 58) 7 patients developed AML and 5 patients MDS. Five of the 12 patients had been treated with HU alone, and 4 patients had received both HU and BU. In the non-HU-treated group (n = 25) 1 patient with PV developed acute myeloid leukemia (AML). This patient had only been treated with phlebotomies. It is concluded that treatment with HU is leukemogenic, with an incidence of AML and MDS of approximately 14% when used alone. The incidence is markedly increased to about 30% when HU is preceded by treatment with BU. HU is not recommended for use in younger patients, in whom non-leukemogenic agents such as alpha-interferon and anagrelide should be used instead.

Acute Disease↗
PubMed2004

Mechanism for induction of hydroxyurea resistance and loss of latent EBV genome in hydroxyurea-treated Burkitt's lymphoma cell line Raji.

Hydroxyurea (HU), as an inhibitor of ribonucleotide reductase (RR) through interaction with the R2 component, has been used in the treatment of malignancies. Recently, therapeutic strategies in Epstein-Barr Virus (EBV)-targeted lymphoma have been reported. In order to study the effect of HU on EBV, infected Burkitt's lymphoma (BL) Raji cells were passaged in medium containing 50 microM HU for more than 2 months. EBV DNA was eliminated in about 40% of the cells in the HU-treated cultures. The cells were cloned from such cultures, and only EBV-positive clones could be isolated in 102 examined clones. No differences were observed in the EBV-latent state, EBV-gene expression, or cell growth between HU-untreated Raji cells and HU-treated clones. However, relative to parental Raji cells, the HU-treated Raji clones were almost eight times resistant to growth inhibition by HU according to the ID50 value, and the expression of the R2 component of RR increased more than two to three times. These results indicate that HU not only efficiently eliminates the EBV genome from Raji cells but also induces HU resistance. HU resistance was accompanied by over-expression of the R2 component of RR. However, the HU-resistant clones were sensitive to gemcitabine, another inhibitor of RR, and this seems highly relevant to chemotherapeutic combination in the use of these drugs.

Antiviral Agents↗