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PubMed2005

The measurement of urinary hydroxyurea in sickle cell anaemia.

Hydroxyurea is increasingly used in the treatment of sickle cell disease (SCD) although there is little evidence on how best to monitor treatment and compliance. It is also not known why 10-50% patients do not benefit from the drug and whether some of this resistance is because of pharmacokinetic factors. We have developed an assay using mass spectrometry (MS) to measure urinary concentrations of hydroxyurea. We have used this assay to study 12 children and six adults with SCD taking hydroxyurea and found that urinary hydroxyurea was present for at least 12 h following tablet ingestion. Thirty-five urine samples were analysed that were expected to contain hydroxyurea, based on the reported timing of the last dose and hydroxyurea was detected in 29 (83%) of these. There were also marked differences in urinary hydroxyurea concentrations, suggesting pharmacokinetic variability may explain some of the differences in response to hydroxyurea. Urine samples were also analysed by MS for penicillin metabolites and 43 of the 57 (75%) contained phenoxyacetate, suggesting the ingestion of penicillin within the last 12 h. These assays are potentially useful to study hydroxyurea metabolism further, develop optimal dosing regimes and monitor compliance with treatment.

Adolescent↗

PubMed2006

Influence of hydroxyurea on imatinib mesylate (gleevec) transport at the mouse blood-brain barrier.

The combination of imatinib mesylate and hydroxyurea provides a therapeutic benefit in patients with glioblastoma, although each drug is not effective when used alone. The increase of brain delivery of one or both drugs has been suggested to be a potential cause of this therapeutic benefit. The cross-influence of hydroxyurea and imatinib on their respective brain distribution was examined in mice and rats. We used in situ brain perfusion in mice to determine whether these two drugs have an influence on their respective initial transport across the blood-brain barrier. The brain penetration of hydroxyurea, assessed by its brain uptake clearance, Knet, was low in mice (approximately 0.10 microl/g/s) and not modified by coperfusion of imatinib (0.5-500 microM). Likewise, the brain penetration of imatinib was low (Knet, 1.39 +/- 0.17 microl/g/s) and not modified by direct coperfusion of hydroxyurea (0.2-1000 microM) or by intravenous pretreatment with 15 or 1000 mg/kg hydroxyurea. We also examined a potential time-dependent influence of hydroxyurea on imatinib brain distribution after sustained subcutaneous administration in rats using an implantable osmotic pump. The brain penetration of imatinib in rats increased with time, approximately 1.6-fold (p < 0.01) after 7 and 14 days' infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/day), and was not influenced by hydroxyurea. The results of these two sets of experiments indicate that hydroxyurea has no significant influence on the brain distribution of imatinib in mice and rats.

Animals↗

PubMed2001

Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas.

PURPOSE: In vitro low concentrations of hydroxyurea eliminate double-minute chromosomes (dmins) containing amplified drug-resistance genes and oncogenes from cancer cells. This clinical trial investigated whether a noncytotoxic dose of oral hydroxyurea could reduce the number of dmins in cancer cells in patients with advanced ovarian carcinomas. EXPERIMENTAL DESIGN: The high frequency of ascites associated with ovarian cancer facilitated the monitoring of cytogenetic variations with minimal discomfort in patients who required frequent abdominal paracentesis. Sixteen patients with advanced ovarian carcinomas resistant to conventional cisplatin-based and/or paclitaxel chemotherapy and with ascites requiring frequent abdominal paracentesis were entered in this study. A course of treatment consisted of a single oral dose of 80 mg/kg hydroxyurea every 3 days for 6 weeks. Blood and i.p. levels of hydroxyurea were determined. We monitored the variations of dmins in tumor cells taken from serial abdominal paracenteses. RESULTS: The median number of courses administered to the patients was 1 (range, 1--9). In ascites, hydroxyurea concentrations were 610.3 +/- 76.3, 219.8 +/- 85.6, and 86.1 micromol/liter at 4, 24, and 30 h after oral administration, respectively. Eleven (78.6%) of 14 patient specimens contained dmins before therapy. The number of spreads with tumor cells containing dmins were reduced by more than 50% in 5 (45%) of 11 and 3 (60%) of 5 patients at the completion of the first and second course of chemotherapy, respectively. Using tumor cells taken directly from the patients and grown in soft agar, we documented that concentrations of hydroxyurea in ascites were too low to have any cytotoxic effects. No grade 3--4 hydroxyurea-related toxicities nor any objective responses were observed. However, despite the utilization of a low noncytotoxic dose of hydroxyurea, two patients had prolonged stabilization of their disease for 6 and 10 months, respectively, with concomitant decreases in the number of dmins that remained until progression. CONCLUSIONS: This study showed that, in some circumstances, a noncytotoxic dose of hydroxyurea given to patients with ovarian cancer can decrease the number of metaphase spreads containing dmins in cancer cells.

Administration, Oral↗

PubMed1992

Hydroxyurea-induced HbF production in anemic primates: augmentation by erythropoietin, hematopoietic growth factors, and sodium butyrate.

Hydroxyurea, a cell-cycle-specific cytotoxic agent, has been shown to increase fetal hemoglobin (HbF) production. This property makes it an attractive drug for treatment of sickle cell disease and severe beta thalassemia. Its potential efficacy is limited because of a variable and often suboptimal response. Combinations of hydroxyurea and other drugs may induce more clinically significant increases in HbF. We have utilized chronically phlebotomized rhesus monkeys, treated with oral hydroxyurea, to investigate the capacity of several other agents to further augment HbF synthesis. Recombinant human erythropoietin, in super-pharmacologic doses, increased F-reticulocyte production when given on a weekly sequential schedule (3 of 7 days) with hydroxyurea (4 of 7 days), but it was less effective on an alternate day schedule when hydroxyurea was given daily. Neither recombinant human interleukin 3 (IL-3) nor recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), when infused individually, increased F-reticulocytes in animals receiving daily hydroxyurea. Sequential, overlapping infusions of IL-3 and GM-CSF produced a small but statistically significant increase in F-reticulocytes in one of two hydroxyurea-treated animals. Infusions of sodium butyrate produced a substantial augmentation in F-reticulocyte production in animals chronically treated with hydroxyurea. Thus, our studies have identified several agents that may prove useful in combination with hydroxyurea to achieve clinically beneficial levels of HbF.

Administration, Oral↗

PubMed1992

Mechanism of action of hydroxyurea.

Hydroxyurea is well absorbed after oral administration, converted to a free radical nitroxide in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replitase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen. Synergy has also been observed between hydroxyurea and a number of other chemotherapeutic agents, including cytarabine and etoposide. Recently, two new effects of hydroxyurea have been observed: hydroxyurea increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia, and hydroxyurea selectively reduces the level of episomal DNA and thus potentially may reduce drug resistance associated with duplicated genes retained as episomes. Further exploration of the efficacy of hydroxyurea in combination with other therapeutic agents is warranted.

Animals↗

PubMed1988

Cross-resistance patterns in hydroxyurea-resistant leukemia L1210 cells.

Hydroxyurea is an inhibitor of ribonucleotide reductase and is specifically directed at the non-heme iron subunit (which contains the free radical) of this enzyme. Leukemia L1210 cells, grown in the presence of increasing concentrations of hydroxyurea, developed resistance to hydroxyurea. For hydroxyurea, the wild-type L1210 cells required a drug concentration of 85 microM to inhibit cell growth by 50%, and the hydroxyurea-resistant (HU-7-S7) cells required a concentration of approximately 2000 microM. The resistant L1210 cells were cross-resistant to 2,3-dihydro-1H-pyrazolo[2,3-a]imidazole/Desferal. However, these HU-7-S7 cells remained sensitive to 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone and 1-isoquinolylmethylene-N-hydroxy-N'-amino-guanidine tosylate (inhibitors directed at the same subunit as hydroxyurea). The HU-7-S7 cells retained their sensitivity to deoxyadenosine/erythro-9-(2-hydroxy-3-nonyl)adenine and deoxyguanosine/8-amino-guanosine (inhibitors directed at the effector-binding subunit of ribonucleotide reductase). The L1210 cells developed for resistance to hydroxyurea were sensitive to the non-ribonucleotide reductase inhibitors, methotrexate and 1-beta-D-arabinofuranosylcytosine. Ribonucleotide reductase activity was elevated in the HU-7-S7 cells (CDP reductase, 5.5-fold increase; ADP reductase, 13.2-fold increase). The addition of exogenous effector-binding subunit caused much greater stimulation of reductase activities in the extracts from the resistant cells than from the wild-type cells. The reductase activity in cell-free extracts from the resistant cells was inhibited by hydroxyurea, 2,3-dihydro-1H-pyrazolo[2,3-a]imidazole and dATP to the same extent as the activity from the wild-type L1210 cells. These data indicate that resistance to hydroxyurea in these L1210 cells is to some extent related to increased reductase activity. However, the specificity of resistance of these L1210 cells to inhibitors of ribonucleotide reductase depends on the nature of the inhibitor and the subunit at which the inhibitor is directed.

Adenine↗

PubMed1994

A cautionary note regarding hydroxyurea in sickle cell disease.

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

Adult↗

PubMed1997

Hydroxyurea in the treatment of sickle-cell anemia.

Sickle-cell anemia is a congenital hemolytic anemia characterized by sickle-shaped RBCs. The deformed RBCs become distorted and rigid and may occlude small arterioles and capillaries leading to tissue ischemia and infarction. Sickled RBCs are too fragile to withstand the trauma of circulation, and hemolysis occurs after they enter the circulation. RBCs with a high level of Hb F are resistant to sickling. Hydroxyurea has been shown to stimulate Hb F synthesis, leading to a reduction in the incidence of hemolytic and vaso-occlusive manifestations; however, hydroxyurea has no role in the treatment of crises already in progress. The National Heart, Lung, and Blood Institute announced in January 1995 that treatment with hydroxyurea leads to an increase in Hb F production within RBCs and a reduction in the frequency of painful crises in patients with sickle-cell anemia. Although the mechanism by which hydroxyurea increases Hb F is not known, one possible explanation is that hydroxyurea is cytotoxic to the more rapidly dividing late erythroid precursors, leading to the recruitment of early erythroid precursors that have demonstrated increased capacities to produce Hb F. Clinical trials have demonstrated that hydroxyurea results in an increase in Hb F concentrations; however, this increase may not dramatically affect the progressive vascular changes associated with sickle-cell anemia; thus, patients may still experience complications related to sickle-cell anemia. At North Carolina Baptist Hospital in Winston-Salem, NC, compliant patients with sickle-cell anemia are started on hydroxyurea. There are no specific criteria for patient selection or monitoring. The dosage is started at 10-15 mg/kg/d. Platelet count, complete blood count, and Hb F are monitored and hydroxyurea dosages are adjusted accordingly. Although hydroxyurea has been effective in the treatment of sickle-cell anemia, large double-blind, placebo-controlled clinical trials are needed to determine whether the risks of long-term administration outweight the risk of vaso-occlusive disease in untreated patients.

Anemia, Sickle Cell↗

PubMed2006

The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate.

PURPOSE: It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib. METHODS: The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4. RESULTS: In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either. CONCLUSION: The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Hydroxyurea induces recombination in dividing but not in G1 or G2 cell cycle arrested yeast cells.

Hydroxyurea, a chemotherapeutic and radiosensitizing agent, inhibits ribonucleotide reductase, arrests cells in the S-phase and is mutagenic and recombinagenic. In this paper we investigated whether the recombinagenic activity of hydroxyurea is due to the same activity that leads to arrest in the S-phase or to a more direct action on DNA. The effect of hydroxyurea on intrachromosomal and interchromosomal recombination was investigated in dividing and in G1 or G2 cell cycle-arrested cells of the yeast Saccharomyces cerevisiae. Treatment of dividing cells with hydroxyurea resulted in a large increase in recombination frequencies, even at low non-toxic doses. In contrast, in cells arrested in the G1 or G2 phase, hydroxyurea failed to induce recombination, even at 60-fold higher toxic doses. The presence of metabolic activation (S9 mix) did not change the effects of hydroxyurea on recombination. The data suggest that the recombinagenic activity of hydroxyurea may not be due to any direct effect of hydroxyurea on DNA, but may be linked to the inhibition of ribonucleotide reductase causing inhibition of DNA synthesis leading to S-phase arrest and possibly causing recombinagenic lesions.

Antineoplastic Agents↗

PubMed1991

Hydroxyurea versus interferon alfa-2b in chronic myelogenous leukaemia: preliminary results of an open French multicentre randomized study.

In order to compare the effects of interferon versus hydroxyurea for the treatment of chronic myelogenous leukaemia (CML), 58 CML patients, having received no previous treatment, were randomized into two treatment groups (hydroxyurea or interferon) for an open multicentre study from 1 May 1987 until 1 July 1990. Fifty patients were evaluable: 24 in the interferon group and 26 in the hydroxyurea group. Haematological response was obtained in 16/24 interferon-treated patients and 23/26 hydroxyurea patients. Failure to obtain haematological remissions occurred in eight of 24 interferon-treated patients and in three of 26 hydroxyurea patients. Four interferon-treated patient failures and one hydroxyurea-treated failure were due to drug intolerance. Progression occurred in one interferon-treated patient and in three patients given hydroxyurea. Fourteen of 16 patients in the interferon group and 17/23 in the hydroxyurea group continue on study and show no progression.

Adult↗

PubMed2004

Catalase-mediated nitric oxide formation from hydroxyurea.

Hydroxyurea reduces the incidence of painful crises in patients with sickle cell disease and has recently been approved for the treatment of this condition. A number of in vitro studies show that the oxidation of hydroxyurea results in the formation of nitric oxide, which also has drawn considerable interest as a sickle cell disease therapy. While patients on hydroxyurea demonstrate elevated levels of nitric oxide-derived metabolites, little information regarding the site or mechanism of the in vivo conversion of hydroxyurea to nitric oxide exists. Chemiluminescence detection experiments show the ability of catalase to catalyze the formation of nitrite and nitrate from hydroxyurea. Spectroscopic studies show that the reaction of hydroxyurea and catalase in the presence of a hydrogen peroxide generating system produces a ferrous-NO catalase complex. Trapping studies indicate the intermediacy of a nitroso species during this reaction. The proposed mechanism for this conversion includes initial hydrogen peroxide-dependent oxidation of hydroxyurea by catalase to form the nitroso species, hydrolysis of this nitroso species to produce nitroxyl, and reductive nitrosylation of the ferric heme of catalase by nitroxyl to yield the ferrous-NO catalase complex. Addition of Angeli's salt, a nitroxyl donor, to ferric catalase also produces the ferrous-NO catalase complex. Spectroscopic studies show that the ferrous-NO catalase complex releases nitric oxide as judged by the oxyhemoglobin assay and an NO specific EPR specific trap. These results demonstrate nitric oxide production from the ferric catalase oxidation of nitroxyl and identify a catalase-mediated pathway as a potential source of nitric oxide production from hydroxyurea.

Catalase↗

PubMed2003

UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia.

Hydroxyurea therapy reduces hemolysis and decreases serum bilirubin levels in children and adults with sickle cell anemia (SCA) and may therefore help prevent the development of cholelithiasis in this patient population. We recently reported that a promoter polymorphism in the uridine diphosphoglucuronate glucuronosyltransferase 1A (UGT1A) gene affects steady-state bilirubin levels and the incidence of gallstones in children with SCA. We have now analyzed the influence of the UGT1A genotype on the therapeutic response to hydroxyurea. A large cohort of children with SCA taking hydroxyurea therapy at the maximum tolerated dose demonstrated significant reductions in hemolysis independent of UGT1A promoter polymorphism genotype, but the hydroxyurea-related decreases in serum bilirubin levels were significantly different. Children with the wild-type 6/6 UGT1A genotype demonstrated normalized bilirubin levels with hydroxyurea therapy, but children with the heterozygous 6/7 or abnormal 7/7 genotypes did not. Children with the abnormal 7/7 genotype, which confers the phenotype of Gilbert syndrome, had bilirubin levels greater than 3 mg/dL despite full-dose hydroxyurea therapy. These data indicate the UGT1A promoter polymorphism is a powerful nonglobin genetic modifier in SCA that influences serum bilirubin both at baseline and on hydroxyurea therapy. UGT1A promoter polymorphisms may therefore influence the ability of hydroxyurea to prevent gallstone formation in patients with SCA.

Anemia, Sickle Cell↗

PubMed1993

Role of antioxidant enzymes in the induction of increased experimental metastasis by hydroxyurea.

BACKGROUND: Treatment of tumor cells with hydroxyurea and other DNA-damaging agents has been shown to increase the experimental metastatic potential of these cells. PURPOSE: We sought to elucidate some of the biochemical and genetic changes that promote tumor cell metastasis in hydroxyurea-treated cells. We hypothesized that drug treatment induces resistance to oxidative damage and that elimination of this resistance reverses the drug-induced experimental metastatic capabilities of tumor cells. METHODS: We examined the effect of hydroxyurea treatment on B16 melanoma cells with respect to experimental metastatic potential, resistance to hydrogen peroxide (H2O2), glutathione peroxidase activity and messenger RNA (mRNA) level, glutathione reductase activity, glutathione levels, glutathione-S-transferase activity, and catalase activity and mRNA level. RESULTS: Hydroxyurea-treated cells were transiently more metastatic following intravenous injection in syngeneic mice and transiently more resistant than untreated cells to exogenous H2O2. Hydroxyurea-induced experimental metastases and H2O2 resistance were eliminated by depletion of intracellular glutathione with buthionine sulfoximine. Glutathione peroxidase activity and mRNA level, glutathione reductase activity, and reduced glutathione levels were all transiently increased in hydroxyurea-treated cells, whereas the increase in glutathione-S-transferase activity was sustained. Catalase activity was modestly increased with no increase in its mRNA levels. CONCLUSIONS: In B16 melanoma cells, experimental metastasis induced by hydroxyurea appears to depend on a process that requires glutathione. Hydroxyurea treatment also induces resistance to exogenous H2O2, which may be due to induction of glutathione and antioxidant enzyme activity. IMPLICATIONS: The role of antioxidants in B16 melanoma cells offers new insights into the metastatic process and the cellular response to chemotherapy.

Animals↗

PubMed1994

In vitro antitumor effect of hydroxyurea on hormone-refractory prostate cancer cells and its potentiation by phenylbutyrate.

Previous clinical trials have suggested that hydroxyurea may possess some activity against prostate cancer. The in vitro antiproliferative activity of hydroxyurea was evaluated in three hormone-refractory prostate cancer cell lines, PC-3, DU-145 and PC-3M. Fifty-percent inhibition of growth in all three cell lines required prolonged (120 h) exposure to hydroxyurea at a concentration of approximately 100 microM. Using pharmacokinetic data obtained during the course of a clinical trial of hydroxyurea, we simulated a dosing regimen that would sustain plasma drug concentrations above 100 microM for 120 h (1 g loading dose, followed by 500 mg every 6 h for 5 days in a 70 kg man). Since this dosing regimen is likely to generate an unacceptable degree of myelosuppression, in vitro combination studies were conducted with hydroxyurea and phenylbutyrate, a new differentiating agent with no myelosuppressive effects. These studies resulted in a reduction of the hydroxyurea concentration necessary for 50% growth inhibition (50 microM of hydroxyurea plus 0.5 mM of phenylbutyrate). A regimen designed to achieve that hydroxyurea concentration (400 mg loading dose, followed by 200 mg every 6 h for 5 days) should be clinically achievable. Based on these results, this combination deserves further evaluation in patients with stage D prostate cancer.

Cell Division↗

PubMed2002

Higher rate of toxicity with no increased efficacy when hydroxyurea is added to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection.

Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p >.1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p <.05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.

Adult↗

PubMed1994

Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication.

Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis--and, consequently, DNA synthesis--by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus-type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and activated) and macrophages, as well as in blood cells infected in vivo obtained from individuals with acquired immunodeficiency syndrome (AIDS). The antiviral effect was achieved at nontoxic doses of hydroxyurea, lower than those currently used in human therapy. Combination of hydroxyurea with the nucleoside analog didanosine (2',3'-dideoxyinosine, or ddl) generated a synergistic inhibitory effect without increasing toxicity. In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants. Hydroxyurea therefore appears to be a possible candidate for AIDS therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Isolation and initial characterization of a series of Chlamydia trachomatis isolates selected for hydroxyurea resistance by a stepwise procedure.

Chlamydiae are obligate intracellular bacteria that are dependent on eukaryotic host cells for ribonucleoside triphosphates but not deoxyribonucleotide triphosphates. Ribonucleotide reductase is the only enzyme known to catalyze the direct conversion of a ribonucleotide to a deoxyribonucleotide. Hydroxyurea inhibits ribonucleotide reductase by inactivating the tyrosine free radical present in the small subunit of the enzyme. In this report, we show that Chlamydia trachomatis growth is inhibited by hydroxyurea in both wild-type mouse L cells and hydroxyurea-resistant mouse L cells. Hydroxyurea was used as a selective agent in culture to isolate, by a stepwise procedure, a series of C. trachomatis isolates with increasing levels of resistance to the cytotoxic effects of the drug. One of the drug-resistant C. trachomatis isolates (L2HR-10.0) was studied in more detail. L2HR-10.0 retained its drug resistance phenotype even after passage in the absence of hydroxyurea for 10 growth cycles. In addition, L2HR-10.0 was cross resistant to guanazole, another inhibitor of ribonucleotide reductase. Results obtained from hydroxyurea inhibition studies using various host cell-parasite combinations indicated that inhibition of host cell and C. trachomatis DNA synthesis by hydroxyurea can occur but need not occur simultaneously. Crude extract prepared from highly purified C. trachomatis reticulate bodies was capable of reducing CDP to dCDP. The CDP reductase activity was not inhibited by monoclonal antibodies to the large and small subunits of mammalian ribonucleotide reductase, suggesting that the activity is chlamydia specific. The CDP reductase activity was inhibited by hydroxyurea. Crude extract prepared from drug-resistant L2HR-10.0 reticulate bodies contained an elevation in ribonucleotide reductase activity. In total, our results indicate that C. trachomatis obtains the precursors for DNA synthesis as ribonucleotides with subsequent conversion to deoxyribonucleotides catalyzed by a chlamydia-specific ribonucleotide reductase.

Adenine↗