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PubMed1981

Schedule-dependent synergism of combinations of hydroxyurea with adriamycin and 1-beta-D-arabinofuranosylcytosine with adriamycin.

The lethal effects of combinations of adriamycin (ADR) and either hydroxyurea (HU) or 1-beta-d-arabinofuranosylcytosine (ara-C) were studied in relation to drug-scheduling interval in Sarcoma 180 cells grown in vitro. Drug lethality was determined by cell cloning in soft agar. Serial kinetic changes induced by a priming dose of HU or ara-C were monitored by flow cytometry and related to schedule-dependent cell killing by ADR. All drug exposures were for 1 hr. When ADR was given together with either HU or ara-C, cell log kill was additive. However, when ADR was given after exposure to either HU or ara-C, cell killing was increased up to 200- to 500-fold, respectively. Maximum schedule-dependent synergism was observed at a drug-scheduling interval of 2 hr; schedule-dependent synergism decreased as the interval between drugs was increased beyond 2 hr. Schedule-dependent synergism was not observed when the same drug combinations were given in reversed order. Drug-induced changes in the DNA histogram were not seen until 5 hr after HU exposure and 8 hr after ara-C exposure. Thus, the schedule-dependent synergism between ADR and either HU or ara-C cannot be explained by cell cycle blockade with synchronization of cells in S phase.

Animals↗

PubMed1981

Histopathology of reversible cataracts produced by hydroxyurea in vitro.

A DNA synthesis inhibitor, hydroxyurea (HU) (5 X 10(-2) M), was added to the organ culture medium for a rat crystalline lens (male, white Wistar rats weighing 100 g). 1. On the 3rd day, a macroscopic examination revealed diffuse opacity of the posterior capsule. Because of removal of HU from the culture medium on the 3rd day the crystalline lens had become lucid on the 6th day, approximately the same as that of the control on the 6th day. In a histopathological examination, the epithelial cells appeared to maintain a histo-architecture similar to that of the control. Lens fiber swelling was scarce at this time. 2. The crystalline lens cultured with HU showed diffuse opacity of the anterior capsule and localized opacity below the posterior capsule in a macroscopic examination on the 5th day. In histopathological examinations of the same culture, the lens epithelial cells and swelling of the lens fibers had disappeared.

Animals↗

PubMed1981

[Effect of a single dose of hydroxyurea on cell division in the esophageal and lingual epithelium of mice].

The mitotic index (MI), labeling index (LI) and the rate of 3H-thymidine nuclear incorporation (TNI) were revealed to decrease within the first hours after a single injection of hydroxyurea (HU) in doses of 100, 250 or 500 Mg/kg bw. After 9-12 hours the LI and MI exceeded the control level, while the TNI returned to normal. The degree of changes in the cell kinetics was found to depend on the dose of HU. The effect of HU on the proliferating cells proves, as a rule, to be temporary and reversible.

Animals↗

PubMed1980

Synchronization of L1210 leukemia with hydroxyurea infusion and the effect of subsequent pulse dose chemotherapy.

Studies were performed to synchronize L1210 tumor cells in S phase in an effort to maximize the effect of subsequent pulse dose chemotherapy. Hydroxyurea (HU) was administered by continuous iv infusion 5 days after tumor implantation. Perturbation effects on the S-phase cells were measured by serial tritiated thymidine labeling indices. Effects on cell-cycle progression were measured by DNA content distribution analysis using flow cytometry. Synchronization of tumor cells was achieved with HU infusion (48 mg/kg/hour x 24 hours), resulting in 90% of the cells in S phase. Following infusion, synchronous progression of S-phase cells into G2/M and then G1 was apparent from +0 to +10 hours later. The susceptibility of HU-synchronized cells to subsequent chemotherapy was determined by treating mice with cytosine arabinoside (Ara-C), methotrexate (MTX), or Adriamycin (ADR) pulse doses at various intervals following infusion. Synergy, measured by prolongation of survival times, resulted when Ara-C was administered immediately after the end of the infusion. Survival times then decreased as the fraction of cells in S phase decreased. In contrast, the survival times of mice treated with MTX or ADR pulse doses after HU infusion were additive at best and did not correlate with fluctuations in the S phase compartment. Therefore, prior synchronization of tumor cells in S phase was therapeutically advantageous when coupled with appropriately timed Ara-C pulse doses. There was little advantage in combining HU infusion with subsequent MTX or ADR therapy.

Animals↗

PubMedDate not supplied

High-dose cyclophosphamide versus cyclophosphamide, methotrexate, 5-FU, and hydroxyurea (CMFH) in the treatment of stage III non-small cell bronchogenic carcinoma: a randomized trial.

Fifty-eight patients with non-small cell carcinoma of the lung (33 with epidermoid carcinoma, 22 with adenocarcinoma, and three with large cell anaplastic carcinoma) were treated with high-dose cyclophosphamide (CTX) or, alternatively, with CTX, methotrexate, 5-FU, and hydroxyurea (CMFH) in a controlled study. Two partial remissions were achieved (one in each regimen [13%]. Seventeen of 29 patients treated with CTX and 14 of 29 patients treated with CMFH showed no change (differences were not statistically significant). Toxicity was moderate in both regimens. Median survival was 24 weeks for patients treated with CTX and 26 weeks for patients treated with CMFH (differences were not significant). The results show that the therapeutic activity of CMFH is not higher than that of CTX alone.

Aged↗

PubMed1994

Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine.

Hydroxyurea (HU) is currently used in the clinic for the treatment of chronic myelogenous leukemia, head and neck carcinoma, and sarcoma. One of its drawbacks, however, is the development of HU resistance. To study this problem, we developed a HU-resistant human KB cell line which exhibits a 15-fold resistance to HU. The characterization of this HU-resistant phenotype revealed a gene amplification of the M2 subunit of ribonucleotide reductase (RR), increased levels of M2 mRNA and protein, and a 3-fold increase of RR activity. This HU-resistant cell line also expressed a "collateral sensitivity" to 6-thioguanine (6-TG), with a 10-fold decrease in the dose inhibiting cell growth by 50% as compared to the KB parental line. The mechanism responsible for this supersensitivity to 6-TG is believed to be related to an increasingly efficient conversion of 6-TG to its triphosphate form, which is subsequently incorporated into DNA. After passage of the resistant cells in the absence of HU, the cell line reverts. The revertant cells lose their resistance to HU and concomitantly their sensitivity to 6-TG. This phenomenon is due to the return of RR to levels comparable to that of the KB parental cell line. These observations and their relevance to cancer chemotherapy will be discussed in this paper. Our results suggest that a clinical protocol could be designed which would allow for a lower dose of 6-TG to be used by taking advantage of the increased RR activity in HU-refractory cancer patients. Two drugs which display collateral sensitivity are known as a "Ying-Yang" pair. Alternate treatment with two different Ying-Yang pairs is the rationale for the "Ying-Yang Ping-Pong" theory in cancer treatment. This rationale allows for effective cancer chemotherapy with reduced toxicity.

Animals↗

PubMed1994

Fetal haemoglobin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease.

Haematological features of 64 patients suffering from non operable cyanotic congenital heart disease (CCHD) treated with hydroxyurea (HU) were compared with those of 43 patients suffering from the same disorder who had not yet received this drug. Patients with subclinical renal dysfunction were excluded by measuring plasma creatinine levels. MCV and HbF were higher among patients receiving HU, the increase in MCV being cumulative with HU dosage but the rise in HbF dose independent. HbF response to HU was found to be due to the coordinated increase in F-cell and F-reticulocyte production rather than to a selective survival of F-cells. Absence of a relationship between plasma erythropoietin and HbF levels excluded a dominant role of the former in increasing F-cell production and results determined after doubling the HU dosage or immediately after initiating therapy suggested genetic differences to be responsible for the individual variations in Hb F response. No irreversible toxic effects or malignancies were noted in this series of patients. HU was administered for a relatively long period of time, the mean duration of treatment exceeding 5 years, while the study also included patients below the age of 10 years.

Adolescent↗

PubMed1995

Altered regulation of message stability and tumor promoter-responsive cis-trans interactions of ribonucleotide reductase R1 and R2 messenger RNAs in hydroxyurea-resistant cells.

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The activity and message levels of the enzyme are elevated in cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, and this appears to be mediated through specific cis elements in the 3'-untranslated region of the R1 and R2 mRNAs that interact with R1 and R2 binding proteins called R1BP and R2BP, respectively. Hydroxyurea-resistant cells with increased R1 and R2 message levels were observed to have increased R1 and R2 message half-lives. This was accompanied by alterations in R1 and R2 3'-untranslated region cis-trans interactions, as judged by band shift and UV cross-linking assays, in which R1BP and R2BP binding was markedly reduced. This first description of mutant mammalian cells altered in message stability regulatory determinants indicates another mechanism for acquiring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important general regulators of ribonucleotide reductase message stability and act as message destabilizing factors.

Animals↗

PubMed1995

Hydroxyurea with continuous infusion paclitaxel, 5-fluorouracil, and concomitant radiotherapy for poor-prognosis head and neck cancer.

Concomitant chemoradiotherapy holds promise in the therapy of advanced head and neck cancer. We have previously reported on the combination of 5-fluorouracil, hydroxyurea, and concomitant chemoradiotherapy administered on an alternate-week basis. In this ongoing study, we are testing the feasibility of adding continuous-infusion paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this combination. Background information and early clinical data are presented.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1-infected individuals.

HIV is known to be present in massive amounts in both resting and actively replicating cells in infected individuals. We tested the combination of didanosine and hydroxyurea, known to suppress viral production in vitro in both of these cell types, in a small number of asymptomatic patients. After 3 months of well tolerated treatment, we observed a large reduction of viral load in the peripheral blood of all 12 patients, down to nonquantifiable levels in 7 of 12 as measured by infectious virus titer, and 6 of 12 as measured by plasma HIV-RNA. In this subgroup of 6 patients, whose baseline HIV-RNA was below 14,000 copies/ml, the median increase in CD4+ count after 90 days of treatment was 244 cells/mm3.

Adult↗

PubMed1993

Hydroxyurea increases fetal hemoglobin in cultured erythroid cells derived from normal individuals and patients with sickle cell anemia or beta-thalassemia.

Hydroxyurea (HU), an inhibitor of DNA synthesis, has been shown to increase fetal hemoglobin (HbF) levels in patients with sickle cell anemia and in some patients with beta-thalassemia. However, until now there have not been good in vitro model systems that simulate this effect for study of the molecular and cellular mechanism(s) involved in perturbing the normal ontogeny of the globin genes. We analyzed the cellular effects of HU using a two-phase liquid culture procedure (Fibach et al: Blood 73:100, 1989) in which human peripheral blood-derived progenitor cells undergo proliferation and differentiation. HU was found to have multiple effects on these cultured cells: (1) an increase in the proportion of HbF produced; (2) a decrease in cell number due to inhibition of cell proliferation; (3) an increase in hemoglobin content per cell (mean corpuscular hemoglobin [MCH]); and (4) an increase in cell size (mean corpuscular volume). The extent of these effects was related to the HU dose and time of addition. When added to cell cultures from normal individuals, 4 days following their exposure to erythropoietin (EPO), 100 mumol/L HU caused a 1.3- to 3.5-fold increase in the proportion of HbF, from 0.4% to 5.2% (mean 1.6) in untreated to 1.5% to 8.2% (mean 3.1) in HU-treated cultures and a 45% +/- 10% increase in MCH but only a 25% +/- 7% decrease in cell number on day 13. Cultures of cells derived from five patients with sickle cell anemia have shown a twofold to fivefold increase in the percentage of Hb F following addition of HU while four patients with beta-thalassemia showed a 1.3- to 6.2-fold increase. We believe that this primary cell culture procedure should prove useful in studying the cellular and molecular mechanisms of pharmacologic induction of HbF and might provide a valuable predictive assay system for evaluation of the response of individual patients with hemoglobinopathies to HU and similar agents.

Anemia, Sickle Cell↗

PubMed1995

The interaction of hydroxyurea and iododeoxyuridine on the radiosensitivity of human bladder cancer cells.

Biochemical modulation of iododeoxyuridine (IdUrd) incorporation into the DNA of tumor cells is a potential clinical strategy to enhance radiosensitivity and to simultaneously differentiate the sensitivity of rapidly proliferating tumor cells and more slowly proliferating adjacent normal tissues to radiation. The interactions of hydroxyurea (HU) and IdUrd were studied in a human bladder cancer cell line, 647V. Exposure of exponentially growing 647V cells to HU concentrations of 10-100 microM for one cell population doubling (24 h) resulted in no cytotoxicity as assessed by clonogenic survival. Flow cytometric analysis showed a significant increase in an early S-phase population after a 12-h exposure but a return to a normal cell cycle distribution after a 24-h exposure to 100 microM HU. Incorporation of IdUrd into DNA was increased 2-fold by coincubation with HU (100 microM) and a clinically achievable concentration of IdUrd (2 microM) for 24 h. To elucidate the mechanism of modulation, IdUTP pools were compared in 647V cells treated with 2 microM IdUrd with or without 100 microM HU. A 2-fold increase in IdUTP pools was evident within 2 h when this drug combination was used. With the use of multivariate statistical analysis, the radiosensitivity of 647V cells was compared after a 24-h exposure to various concentrations of IdUrd (0 and 2 microM) and HU (0, 10, and 100 microM). A 24-h exposure to 100 microM HU alone or to 2 microM IdUrd alone before irradiation resulted in significant (P < 0.02) radiosensitization with sensitizer enhancement ratios of 1.15 and 1.27, respectively. A 24-h exposure to 100 microM HU + 2 microM IdUrd resulted in even more significant (P = 0.001) radiosensitization, which was found to be a greater than additive response (sensitizer enhancement ratio, 1.76 observed compared with 1.37 expected). No radiosensitization was found with a 12-h exposure to 100 microM HU alone. The mechanism of biochemical modulation of IdUrd by a noncytotoxic dose of HU is proposed as increasing the IdUTP pools by stimulating enzymes in the thymidine salvage pathway and subsequently enhancing IdUrd incorporation and radiosensitization.

Cell Cycle↗

PubMed1994

[A case of chronic neutrophilic leukemia accompanied with severe bone marrow fibrosis which was effectively treated by hydroxyurea].

A 57-year-old man was admitted to hospital because of leukocytosis. He showed mild splenomegaly and, laboratory studies revealed elevated mature neutrophil count without morphological abnormality, mild anemia and elevated neutrophil alkaline phosphatase score. The serum granulocyte colony stimulating factor concentration was below 30 pg/ml. Bone marrow was a dry tap, and biopsy specimen revealed severe fibrosis. The peripheral blood karyotype was 46, XY with no rearrangement of bcr-abl. The patient was diagnosed as having chronic neutrophilic leukemia (CNL) with bone marrow fibrosis. He was successfully treated with hydroxyurea (HU) 1000 mg/day. The peripheral blood leukocyte was decreased to the normal level and, the bone marrow biopsy specimen changed mild fibrosis. During the follow up period of 11 months, the neutrophil count was well controlled without any side effect. This is a rare case of CNL accompanied with bone marrow fibrosis which was effectively treated by the administration of HU.

Humans↗

PubMed1994

Iron chelators hydroxyurea and bathophenanthroline disulfonate inhibit DNA synthesis by different pathways.

We previously showed that thrombin-stimulated DNA synthesis in CCL 39 cells was inhibited by hydroxyurea (HU) and bathophenanthroline disulfonate (BPS) (Proc. Natl. Acad. Sci. USA, in press). A clear difference exists between these two inhibitors. Inhibition mediated by HU was immediate and must be present in the culture medium. BPS was equally effective when it was present in the medium or after preincubation, but it required at least 12 h to achieve maximal effect. The permeable form 1,10 phenanthroline had the same inhibitory effect in short-term incubations that BPS. Moreover, 1,10 phenanthroline was cytotoxic in long-term incubations indicating that the site of BPS inhibition was outside the cell. Further, long-term incubations with HU did not affect the ability of the cell to reinitiate DNA synthesis after removal of the chelator.

Animals↗

PubMed1995

Optimization of the potency and duration of action of N-hydroxyurea 5-lipoxygenase inhibitors.

As in vitro glucuronidation assay and several biochemical assays were utilized to discover potent new N-hydroxyurea-containing 5-lipoxygenase inhibitors with long durations of action. The best of these, A-78773, is a racemic mixture of two enantiomers. These enantiomers were purified and the R(+)-enantiomer A-79175 was found to be superior to the S(-)-enantiomer with respect to in vitro metabolism and duration of action in the monkey. A-79175 was a potent selective inhibitor of 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemic homogenates (IC50 = 54 nM) and of calcium ionophore-induced leukotriene B4 (LTB4) formation in purified human polymorphonuclear leukocytes (IC50 = 25 nM) and human whole blood (IC50 = 80 nM). The compound inhibited LT formation in the rat with oral ED50s of 1 to 2 mg/kg. It also was a potent inhibitor of edema and inflammatory cell influx in rats and mice. A-79175 was resistant to glucuronidation and had an elimination half-life of nearly 9 hr in cynomolgus monkeys. A-79175 inhibited ex vivo LTB4 formation by monkeys for extended periods. A single 0.5-mg/kg oral dose gave > 50% inhibition of calcium ionophore-induced LTB4 formation ex vivo for 12 hr. A good correlation was found between the elimination half-life for A-78773 and its enantiomers in cynomolgus monkeys and humans. These data indicate that A-79175 is a promising long-acting agent that should be useful to delineate the importance of LTs in animal and human studies.

Animals↗

PubMed1994

Treatment of beta-thalassemia with hydroxyurea (HU)--effects of HU on globin gene expression.

A newly developed method of RT-PCR/competitive PCR for measuring the relative and absolute content of globin mRNAs as well as micro-globin chain biosynthetic assay have been used to study the alterations of globin gene expressions in the patients with beta-thalassemia pre- and post-hydroxyurea (HU) treatment. It was found for the first time that HU had the effect of enhancing beta-globin gene expression in some patients. Two cases with beta-thalassemia who were subjected to HU treatment for over two years showed a marked increase in beta-globin mRNA level and beta-globin chain synthesis, resulting in more effective erythropoiesis and the alleviation of clinical symptoms.

Adult↗

PubMed1994

[Treatment of chronic myeloid leukemia using alpha-interferon and hydroxyurea. Study of 30 cases].

PURPOSE: To evaluate the efficacy of the combination, alpha-interferon (IFN)-hydroxyurea (HU) in the treatment of patients with Philadelphia positive chronic myelogenous leukaemia (Ph'-CML). PATIENTS AND METHODS: A prospective study was started in 1988 in which 30 patients with chronic phase, low-risk Ph'-CML, according to Kantarjian's staging system, were included. They were treated with IFN at a dose of 5 MU/m2 subcutaneously twice a week plus HU in doses between 0.5 and 3 g/m2/day. The clinic and biologic controls performed twice a month included granulocyte alkaline phosphatase, and cytogenetic studies of bone-marrow and peripheral blood were carry out every third month. The quality and duration of haematologic and cytogenetic remissions were evaluated, along with the untoward effect of the treatment. Survival was estimated in accordance to the Kaplan Meier method. RESULTS: The mean age was 49 years (range: 17-70) and the M/F ratio was 18/12. The median follow-up was 51 months (range: 8-89). Twenty patients were in early- and four late-chronic phase. Complete haematological remission (CHR) was achieved in 26 patients (87%) with a median of 52 months and an estimated global median survival of 81 months. Cytogenetic response was seen in 11 patients (52%) of the 21 who were evaluable after 11 months of treatment. Disappearance of Ph' (complete cytogenetic response) was seen in 6 cases (28%). The incidence of early blast crisis in the first three years was, respectively, 0%, 3% and 6%. The treatment toxicity was negligible in most cases, having to suppress the treatment only in one patient due to persistent fever. CONCLUSIONS: The association of IFN and HU is effective and well tolerated in patients with low-risk CML, and it improves survival in CHR and overall survival.

Adolescent↗

PubMed1994

Anti-human immunodeficiency virus type 1 activity of hydroxyurea in combination with 2',3'-dideoxynucleosides.

The effects of hydroxyurea (HU), an inhibitor of ribonucleotide reductase, on the replication of human immunodeficiency virus type 1 (HIV-1) in activated peripheral blood mononuclear cells were studied. The inhibition of HIV-1 replication by HU alone was dose dependent, with a 90% inhibitory concentration of 0.4 mM, a plasma concentration tolerated by patients with oncological diseases. HU at lower concentrations (< 0.1 mM) was found to potentiate the antiviral activity of 2',3'-dideoxyinosine (ddl), 3'-azido-2',3'- dideoxythymidine, and 2',3'-dideoxycytidine against HIV-1, with the potentiation being ddl greater than 3'-azido-2',3'- dideoxythymidine = 2',3'-dideoxycytidine. In the presence of 0.1 mM HU, the 90% inhibitory concentration of ddl was reduced by 6-fold in activated peripheral blood mononuclear cells. The potentiating effect of HU on ddl action was time dependent, with the greatest inhibition of HIV-1 growth being seen when HU was present during and after virus adsorption, i.e., apparently coinciding with the time of proviral DNA synthesis. A brief incubation of activated cells with HU and ddl at low concentrations before virus exposure reduced p24 production by > 50%. Analyses using high performance liquid chromatography and enzymatic assays suggested that the greater degree of potentiation by HU of the action of ddl, compared with the other dideoxynucleosides, is due to the more effective inhibition by HU of dATP synthesis, compared with the synthesis of the other deoxynucleoside triphosphates (dGTP, dTTP, and dCTP). The present study suggests that, for appropriate agents, pharmacological reduction of deoxynucleoside triphosphate levels represents a potential therapeutic approach for inhibition of HIV-1 replication.

Antiviral Agents↗