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PubMed1983

Hydroxyurea inhibits also the syntheses of thymine nucleotides and methionine in the cells of Escherichia coli.

Hydroxyurea not only inhibited the reduction of ribonucleotides, but also gave rise to need of exogenous methionine and thymidine for full growth in the cultures of Escherichia coli K12. In vitro the drug inhibited the formation of 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase in the cell extracts, which suggests that this reaction is a secondary target of hydroxyurea in the cells of E. coli. The syntheses of thymine nucleotides and methionine were also the most sensitive targets of hydroxylamine in the cultures of E. coli.

Escherichia coli↗

PubMed1984

[Effect of hydroxyurea on the number of hematopoietic stem cells, stromal cell precursors and cell precursors of thymus lymphoid tissue in the bone marrow of mice during aging].

The concentration of hemopoietic stem cells (colony-forming cells in the spleen - CFC-S) decreases in the bone marrow of CBA mice during ageing, whereas the concentration of precursors for stromal fibroblasts (colony-forming cells for fibroblasts-CFC-F) increases. The total numbers of nucleated cells, CFC-S and CFC-F in the bone marrow of old mice essentially increase. Hydroxyurea, administered in vivo, does not effect the concentration of CFC-S, but it increases CFC-F concentration in the bone marrow of mice. Hydroxyurea produces just the same suppressive effect on the numbers of nucleated cells, CFC-S and CFC-F in the mice of different ages, and stimulates the capacity of bone marrow donors to repopulate the thymus of the irradiated young recipients.

Aging↗

PubMed1978

Cell kinetics of erythroid colony-forming cells (CFU-E) studied by hydroxyurea injections and sedimentation velocity profile.

Cell kinetic characteristics of murine CFU-E were assessed by measuring femoral marrow CFU-E survival rates after injection of hydroxyurea at from 2 to 48 h before marrow collection. The results are compatible with the concept that the CFU-E represent a homogeneous non-selfsustaining population comprised of cells belonging to a single differentiation stage. Their cell cycle length was estimated to be 10 h. Marrow cells were also subjected to separation by velocity sedimentation, and the effect of preceding hydroxyurea injections on the distribution profile of CFU-E was ascertained. Variations in cell size of CFU-E were interpreted to represent CFU-E in various phases of their cell cycle. CFU-E in either G1, S or G2 at the time of their removal from the marrow were capable of forming erythroid colonies in vitro, but it appears that the CFU-E lost this capacity after completing their cell cycle within the marrow of the intact mouse.

Animals↗

PubMed1984

[Characteristics of hepatocyte proliferation in the regenerating rat liver with hydroxyurea synchronization of the proliferative processes].

5-week old rats underwent a partial hepatectomy (2/3 of the liver was removed). The operated rats were repeatedly injected hydroxyurea, within 9-24 or 12-24 hours following operation. Proliferation of hepatocytes and non-parenchymal cells in the regenerating liver was studied. Five or six injections of hydroxyurea increased the labelling index of hepatocytes up to 62.5% and induced proliferation of bile duct cells significantly.

Animals↗

PubMed1984

Synergistic inhibition of leukemia L1210 cell growth in vitro by combinations of 2-fluoroadenine nucleosides and hydroxyurea or 2,3-dihydro-1H-pyrazole[2,3-a]imidazole.

9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A) and 2-fluoro-2'-deoxyadenosine (2-FdAdo) were potent inhibitors of L1210 cell growth in culture. Even though these 2-fluoroadenine nucleosides are very poor substrates for adenosine deaminase, erythro-9-(2-hydroxyl-3-nonyl)adenine potentiated the growth-inhibitory properties of 2-FdAdo but not 2-F-ara-A in a synergistic manner. 2-FdAdo and 2-F-ara-A inhibited the conversion of [3H]cytidine to deoxycytidine nucleotides and incorporation into DNA, suggesting that ribonucleotide reductase was an intracellular site of action. 2-F-ara-A (6 microM) in combination with 2,3-dihydro-1H-pyrazole[2,3-a]imidazole gave synergistic inhibition of L1210 cell growth. At lower concentrations of 2-F-ara-A, the inhibition by this combination was only additive. The addition of Desferal to the combination of 2-F-ara-A plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole provided a strong synergistic combination. Similar results were obtained with combinations which included F-ara-A, hydroxyurea, and Desferal. The combinations of 2-FdAdo plus 2,3-dihydro-1H-pyrazole[2,3-a]imidazole or hydroxyurea gave strong synergistic inhibition of L1210 cell growth, even at the lowest concentration of 2-FdAdo (0.6 microM) studied. The presence of Desferal in the combination served to further potentiate the synergism.

Animals↗

PubMed1983

Hydroxyurea inhibits thymidine kinase activity in developing rat cerebellum.

Hydroxyurea when injected intraperitoneally into rats either as a single dose or as three consecutive daily doses, markedly inhibited thymidine kinase activity in cerebellum on 7th day. The inhibitory effect of the drug was found to be both dose and time dependent. The drug has however, failed to exert any inhibitory action when added to the reaction mixture in vitro. It is concluded that the well established inhibition on DNA synthesis by hydroxyurea may not be solely due to its action on ribonucleotide reductase (EC 1.17.4.1) but probably due to its interference at several other sites including thymidine kinase.

Animals↗

PubMed1983

Hydroxyurea inhibits thymidine kinase activity in developing rat cerebellum.

Animals↗

PubMed1983

Transforming activities of methotrexate, hydroxyurea and 5-fluorouracil in different cell systems.

The transforming ability of methotrexate, hydroxyurea and 5-fluorouracil was studied in mass cultures of embryo cells from BN/a, DBA/2 and Swiss mice. As estimated by virological methods the cells from BN/a mice were infected persistently with ectromelia virus. In parallel a quantitative transformation assay with a cloned BALB/3T3 cell line was employed. Oncogenic transformation could be induced repeatedly in mass cultures from BN/a mice after treatment with every of chemotherapeutic agents studied. Neither of the drugs induced transformation in the cultures deriving from two other strains of mice. In the cloned BALB/3T3 cell line from the three drugs tested only methotrexate induced the appearance of transformed foci, however, the yield of transformants was very low. It has been concluded that under the employed experimental conditions the transforming ability of hydroxyurea and 5-fluorouracil could be expressed exclusively in the cells infected with ectromelia virus. The transforming ability of methotrexate seems to depend either on the presence of viral infection or on the properties of cells enabling additional events necessary for transformation.

Animals↗

PubMed1978

Erythroid "bursts" in semi-solid agar diffusion chambers: effect of cyclophosphamide administration to host and of hydroxyurea to donor animals.

Growth of erythroid bursts was induced in peritoneal diffusion chambers in a semi-solid agar medium. Mice of the "Sabra" strain received single i.p. injections of cyclophosphamide (45 mg/kg) 24 h prior to implantation of chambers. Rats of the Hebrew University strain, used as donors, received single i.p. injections of hydroxyurea (400 mg/kg), 9 h prior to being killed. Ten to fourteen days after chamber implantation, several erythroid colonies of ten to several hundred cells developed in the semi-solid agar medium. The erythroid cells in the colonies were benzidine-positive and at various stages of maturation. We suggest that growth of erythroid "bursts" in diffusion chambers, in hosts which had not received any specific erythropoietic stimuli, was made possible by a high concentration of BFU-E in the door marrow. The BFU-E enriched rat bone marrow resulted from administration of hydroxyurea which, after preferentially killing erythroblasts in cycle, stimulated mobilization of stem cells for the replenishment of the depleted compartment.

Agar↗

PubMed1982

Hydroxyurea increases in vitro, antigen-independent B cell development in bone marrow.

The fluorescence-activated cell sorter and Coulter counter were used to study the effect of hydroxyurea in vitro in B cell development in 24 hr cultures of adult mouse bone marrow. This agent, which kills cells in the S phase of the cell cycle, caused a 40-70% increase in the absolute number of B cells in bone marrow cultures as compared with untreated cultures. There was also an increased response to the B cell mitogen, bacterial lipopolysaccharide, as measured by the stimulation index for 3H-thymidine incorporation. Hydroxyurea in vitro increased B cells numbers in fetal liver which contains pre-B cells, but not in lymph nodes or spleen which lack these cells.

Animals↗

PubMed1980

[Modifications in the feeding behavior of the rat, induced by antimitotic drugs: effects of hydroxyurea].

The effects of Hydroxyurea treatment on food intake and on the self-selection between a protein free diet and a complete one are different from those observed during Cyclophosphamide and Mustine Hydrochloride treatment and appear to be similar to those observed during Methotrexate treatment; these may be referred exclusively to a toxic action of the drug on the liver and on the mucous membranes of digestive apparatus. The urea, a product of Hydroxyurea metabolism, does not seem to induce modifications on food intake both as to the quantitative and qualitative aspect.

Animals↗

PubMed1994

Experimental therapy of sickle cell disease. Use of hydroxyurea.

PURPOSE: Therapy of sickle cell disease with hydroxyurea is experimental. PATIENTS AND METHODS: We have begun a randomized blinded clinical trial to determine its clinical utility. The efficacy of this drug is unproved and its risks, which include mutagenesis, teratogenesis and carcinogenesis, are poorly understood. These risks are explicitly stated in our consent forms. A significant number of patients who are asked to enroll refuse to enter the study. This refusal is probably because of individual variations in perception of risk and personal inconvenience, as well as differences in perception of personal benefit. We have a few hints as to which patients are more likely to produce increased amounts of fetal hemoglobin, but our findings do not indicate which patients are most likely to show a good clinical response. RESULTS: Our study group decided not to treat patients under 18 years of age with hydroxyurea until clinical efficacy of the drug is proved in adults. We have criteria for selecting patients for entry into our ongoing study, but the criteria are based more on study design than on an estimate of present or future severity of the manifestations of sickle cell disease. CONCLUSIONS: Features of our previous study and results of the present trial may be helpful in defining indications for bone marrow transplantation in children with sickle cell disease.

Anemia, Sickle Cell↗

PubMed1995

Longitudinal melanonychia induced by hydroxyurea: four case reports and review of the literature.

Although the occurrence of skin lesions during long-term hydroxyurea therapy is well known, longitudinal melanonychia (LM) are more rarely described. In the present paper, we report four cases of LM associated with skin lesions induced by long-term daily hydroxyurea therapy (4 to 10 years), characterized by two uncommon aspects: late onset (2.5 to 5 years) and predominance of toenail involvement in three cases.

Adult↗

PubMed1995

[Clinical pharmacology of hydroxyurea].

Hydroxyurea, an antineoplastic drug evaluated clinically more than 30 years ago, is still the principal drug in patients with myeloproliferative syndromes. It is suggested now that it should be used as initial therapy for chronic myelogenous leukemia. Recently hydroxyurea is used in the treatment of patients with sickle cell disease. It has been shown to augment production of fetal hemoglobin and decrease the propensity of abnormal hemoglobin to polymerize and from the sickle cells in this way.

Anemia, Sickle Cell↗

PubMed1976

In vivo synchronization of murine sarcoma 37 ascites tumor cells by use of hydroxyurea.

Synchrony of DNA synthesis in mouse sarcoma 37 ascites cells was achieved in vivo by injection of 0.75 mg hydroxyurea per gram weight of mouse. DNA synthesis was gauged by comparing 3H-labeled thymidine incorporation, under defined conditions, to total DNA measured colorimetrically. DNA synthesis in the sarcoma 37 cells fell to negligible levels 4 hours after injection and remained at or below levels observed in randomly dividing cells up to 18 hours after injection. A sharp increase in DNA synthesis occurred at 20 hours, followed by a decline again at 22 hours after hydroxyurea injection. DNA synthesis in the intestine remained below control values at 20 hours.

Animals↗

PubMed1994

High-dose cyclophosphamide, thiotepa and hydroxyurea with autologous hematopoietic stem cell rescue: an effective consolidation chemotherapy regimen for early metastatic breast cancer.

Phase I and II trials have demonstrated that high-dose chemotherapy with autologous hematopoietic stem cell rescue is effective 'consolidation' chemotherapy for patients with responding metastatic breast cancer. In this study 26 women with metastatic breast cancer responding to lower dose combination chemotherapy were treated with 18 g/m2 of hydroxyurea added to the widely used combination of cyclophosphamide (CY) 6 g/m2 and thiotepa 600 mg/m2. Hematopoietic stem cell support was provided in the form of previously collected cryopreserved marrow or peripheral blood stem cells if there were malignant cells in the marrow. The patients ranged in age from 25 to 51 years with a median of 43 years. Three patients (12%) died of toxicity, one from Candida pneumonia and the other two from pulmonary and central nervous system bleeding secondary to platelet consumption associated with high fever and renal dysfunction, a syndrome we have seen with approximately the same frequency as a complication of other 'marrow transplant level' chemotherapy. The 1 and 2 year progression-free survivals are projected to be 42% and 27%, respectively. Patients in complete remission or with only residual radiographic abnormalities in bone prior to this therapy had 67% and 58% 1 and 2 year progression-free survival probabilities. High-dose hydroxyurea can safely be added to the CY and thiotepa combination.

Adult↗

PubMed1993

Hydroxyurea and lower leg ulcers.

We report four cases of cutaneous lower leg ulcers associated with hydroxyurea treatment for myeloproliferative disorders. This association has been reported in one other series of patients who had chronic myelogenous leukemia and were treated with hydroxyurea. A review of the literature and survey of possible pathogenetic mechanisms is presented.

Aged↗

PubMed1977

Effect of hydroxyurea and vinblastine on the proliferation of the pluripotential stem cells.

The population of the pluripotential hemopoietic stem cells in mice, i. e. those cells forming colonies in the spleens of lethally irradiated mice (colony forming cells CFc) is proliferating relatively slowly. After a partial damage the population regenerates which is achieved by means of the increased proliferation rate. The effect of damage caused by different doses of hydroxyurea or vinblastine on the proliferation of the CFc has been investigated. CFc population was measured in femur bone marrow after grafting the sample of the bone marrow into the lethally irradiated mice recipients (spleen colony method). The proliferation rate was estimated either according to the magnitude of the fraction of cells synthesizing DNA in the S phase of the cell cycle, or according to the sensitivity of the population to the repeated injections of vinblastine. Data showed that even after very minute damage caused by hydroxyurea the stem cells started to proliferate intensively. The effect was dose dependent. The comparable damage caused by vinblastine had a significantly weaker effect on the proliferation of the stem cells. From the results it is concluded that the proliferation response of the pluripotential stem cells depends on two factors: one being the extent of the damage caused to the hemopoietic tissue and the second the position of the killed cells in the cell cycle.

Animals↗