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PubMed1980

Erythropoietin-independent regeneration of erythroid progenitor cells following multiple injections of hydroxyurea.

It wa shown previously that colony formation in vitro by early erythroid progenitor cells (BFUe) requires sequential stimulation with a specific glycoprotein termed BFA and erythropoietin (EP). The action exerted by BFA was characterized as induction of proliferation in BFUe resulting after several cell divisions in EP-responsive progeny. The present study is directed at detection of EP-independent regulation of erythroid progenitor cells in vivo. Haemopoietic regeneration was induced by multiple administrations of hydroxyurea (HU). The femoral regeneration patterns of haemopoietic stem cells (CFUs), granulocyte/macrophage progenitor cells (CFUgm) and erythroid progenitor cells (BFUe, day 3 BFUe and CFUe) were studied in hypertransfused mice in comparison to nontransfused controls. The results show that (1) the phase of exponential regeneration of none of the cell populations studied is affected by hypertransfusion; (2) each of these cell populations exhibit a distinct regeneration pattern, indicating that they behave as separate functional entities; and (3) the three erythroid cell populations are suppressed by hypertransfusion in the post-exponential phase of regeneration in contrast to CFUs and CFUgm. The results support a two-regulator model of erythropoiesis.

Animals↗

PubMed1981

Inaccuracy of estimations of s phase fraction by reduction in cloning efficiency with hydroxyurea or tritiated thymidine.

The current hypothesis, that the fractional reduction of cloning efficiency in semi-solid culture systems induced by pretreatment of the cells with hydroxyurea (HU) or [3H]TdR equals the fraction of cells initially in S phase, is tested. A lymphoblastoid cell line, SK-L7, with known cell cycle kinetics was exposed to cytotoxic concentrations of HU or suicidal doses of [3H]TdR and then initiated in semi-solid and liquid culture. Although approximately 0.6 of the initial population was in S, 1-hr exposures of HU at concentrations of up to 10(-2) M failed to reduce subsequent cloning efficiency. The 1-hr exposure to HU did not reduce either the immediate cell number or the gross population doubling rate over 24 hr. A 24-hr exposure to 10(-3) M HU reduced the cloning efficiency by approximately 98%, confirming the drug's cytotoxic capability. [3H]TdR at doses of 100 microCi/ml for 20--40 min reduced the cloning efficiency by approximately 60 and 70%, respectively. Although no cytotoxicity immediately after exposure was observed in either case, gross population doubling rate in liquid culture was reduced. While HU failed to reduce subsequent cloning efficiency, [3H]TdR reduced cloning efficiency by approximately the fraction of initial cells in S. The above hypothesis, therefore, cannot be applied naïvely as a technique for quantitating the fraction of a clonogenic cell population in S phase.

B-Lymphocytes↗

PubMed1981

Laser flow cytofluorometric analysis of HTC cells synchronized with hydroxyurea, nocodazole and aphidicolin.

The technique of laser flow cytofluorometry has been used to monitor the arrival in G1 and the subsequent progression through the cell cycle of HTC cells accumulated in metaphase with colcemid alone or after treatment with hydroxyurea and Nocodazole. Under the experimental conditions used in this study, the latter procedure gives much better results, avoiding in particular the extensive formation of micronucleated cells. Aphidicolin, an inhibitor of DNA polymerase, in combination with Nocodazole, provides a useful method to tightly synchronize these cells at the G1/S border.

Animals↗

PubMed1984

Cell-cycle-dependent and -independent damage to rat haemopoiesis by hydroxyurea.

The generally accepted cell-killing effect of hydroxyurea (HU) on S-phase cells, as well as its potential to arrest cells at the G1/S boundary, hardly explain its benefit for application in human chronic myelogenous leukaemia. Studies were therefore performed in rat haemopoiesis in order to quantify the cell-killing effect on various phases of the cell cycle. For this purpose, the [3H]thymidine [( 3H]TdR) labelling index and the specific activity of [3H]TdR in the DNA-synthesizing fraction of cells were determined after a non-cytoreductive dose of 25 mg/kg HU, as well as a medium cytoreductive dose of 100 mg/kg. Furthermore, flow cytometric DNA histograms and absolute as well as differential cell counts of femoral bone marrow were performed after 100 mg/kg HU. The results indicate a predominant cell kill in G1 encompassing almost all 2c cells in the proliferative pool, while the S-phase fraction is not even reduced to half its initial value. The specific activity of [3H]TdR in cells synthesizing DNA, as well as the labelling index after HU show an initial dip and a tendency to recovery, as has been observed in many other cell systems. Instead of a complete restoration, however, there is a second depression of these parameters lasting for at least one cell cycle. The results are interpreted as a partly cell-cycle-dependent and partly independent action of HU in this cell system. The independent component may be attributed to the repeatedly described direct interference of HU with DNA. In rat haemopoiesis, therefore, this direct effect of HU on the DNA strands appears to be much more pronounced than in cell-culture systems and other mammalian tissues. In view of these findings, some caution should be taken in using HU for the determination of the S-phase fraction by way of a suicide experiment.

Animals↗

PubMed1993

Hydroxyurea exposure alters mouse testicular kinetics and sperm chromatin structure.

The effects of hydroxyurea (HU) on testicular cell kinetics and sperm chromatin differentiation were investigated in mice. Whole testis, minced testicular cell suspensions and caudal epididymal sperm cells were obtained at 8 and 29 days after i.p. injections containing 0, 25, 50, 100, 200, 400 and 500 mg/kg HU x 5 days. Testis weights were unaffected by 25 mg/kg HU while 500 mg/kg caused up to a 50% loss of testicular weight by 29 days. Flow cytometrically measured acridine-orange (AO) stained testicular cells revealed altered population ratios at the highest dosages at 8 days and for all dosages except 25 mg/kg HU at 29 days. At 8 days, 400-500 mg/kg HU caused a near depletion of tetraploid cells. Flow cytometry of AO stained sperm, previously treated with acid to potentially induce DNA denaturation, was used to follow the shift from normal chromatin structure to an abnormal form with increased sensitivity to DNA denaturation in situ. The extent of DNA denaturation was quantitated for each cell by the computer-derived value alpha t, alpha t = [red/(red+green) fluorescence]. The flow cytometry measures, standard deviation of alpha t (SD alpha t), mean of alpha t (X alpha t) and cells outside the main peak of alpha t (COMP alpha t), gave similar dose response curves to the sperm head morphology assay. SD alpha t was more sensitive than the X alpha t as a measure of HU-induced alteration of chromatin structure. The major conclusions reached are that HU inhibits DNA synthesis, probably by inhibiting ribonucleotide reductase, causing maturation depletion of pachytene spermatocytes and, subsequently, depletion of meiotic daughter cells and differentiated cell types leading to mature sperm. This inhibition of DNA synthesis is related to an alteration of sperm chromatin structure and abnormal sperm head morphology.

Animals↗

PubMed1993

Simultaneous assessment of migration and proliferation of murine fibrosarcoma cells, as affected by hydroxyurea, vinblastine, cytochalasin B, Razoxane and interferon.

Using porous cell culture chambers, we have simultaneously assessed growth and locomotion of cancer cells to investigate whether certain agents affect cell motility in addition to cell division. First, cells from a murine fibrosarcoma cell line, 1.0/L1, were grown in ordinary flask cultures to determine appropriate cell inocula. Doses of agents were selected to reduce the final 4 day culture cellularity to about 50%, when present during the last two days of culturing. Secondly, the effects of these agents on cell numbers in the porous chambers and on cell migration out of the chambers ('emigration fraction') were recorded. We also examined, using a similar type of porous chamber, whether the agents could affect leucocyte chemotaxis. Hydroxyurea (an inhibitor of DNA synthesis) reduced cancer cell emigration as well as cell growth, without interfering with leucocyte chemotaxis. Cytochalasin B (a microfilament disrupting agent) inhibited cancer cell motility and growth, as well as leucocyte chemotaxis. Vinblastine (a microtubule disrupting agent), at the very low dose chosen, reduced cancer cell growth, but did not consistently affect the migration of either cell type. The experimental anti-metastasis agent Razoxane reduced growth, but had no detectable effects on motility. High doses of natural murine interferon-alpha/beta weakly inhibited both cancer cell growth and locomotion. This motivates for further studies of these and other cytokines, as treatment with agents inhibiting cancer cell locomotion might possibly prevent peri-operative spread of cancer in patients.

Animals↗

PubMed2004

Oral squamous cell carcinoma during long-term treatment with hydroxyurea.

Hydroxyurea (HU) is commonly used for the treatment of chronic myelogenous leukaemia, polycythemia vera and essential thrombocythaemia. Patients receiving HU present a number of side-effects including skin/mucosa changes and tumours. Mucocutaneous abnormalities include xerosis, ichthyosiform lesions, dark brown pigmentation of skin folds and nails, malleolar ulcers, oral mucositis and oral ulcers. Cutaneous squamous/basal cell carcinomas have also often been reported following long-term administration of HU. HU-induced carcinogenesis is due to both the mutagenic potential of this agent and to an impairment of DNA repair mechanisms after damage by external factors such as ultraviolet radiation. Oral cancer following long-term treatment with HU has been reported only once, in a patient with concomitant multiple skin tumours. We present the unique case of a patient with polycythemia vera who developed oral cancer after 15 years of HU therapy.

Aged↗

PubMed1993

The combination of hydroxyurea and leucapheresis in the treatment of chronic myeloid leukaemia in pregnancy.

Treatment of malignancy during pregnancy is difficult because of the potential teratogenicity of chemotherapeutic agents. Leucapheresis was employed in the initial management of a pregnant patient with chronic myeloid leukaemia. It was subsequently replaced with oral hydroxyurea during the second trimester. Successful delivery of a live male infant was achieved and the child has normal growth and development to date.

Adult↗

PubMed2006

Hydroxyurea therapy increases plasma erythropoietin in patients with essential thrombocythaemia or polycythaemia vera.

The determination of serum/plasma erythropoietin (EPO) concentration has gained widespread use in the diagnosis of polycythaemia vera (PV). A reduced EPO concentration in a newly diagnosed essential thrombocythaemia (ET) seems to be a risk factor for thromboembolic events. In this study plasma EPO concentration was determined before and after initiated hydroxyurea (HU) therapy, 14 patients with PV or ET were included. After 1 month on HU therapy 11 of 14 patients had increased their EPO concentration compared with prior to medication. The plasma EPO was increased in all, except one patient, after 4 months HU therapy. If EPO is incorporated in the diagnostic or prognostic procedures it should be determined before myelosuppressive therapy is initiated.

Aged↗

PubMed2006

Effects of hydroxyurea on malaria, parasite growth and adhesion in experimental models.

We recently raised concern over using hydroxyurea (HU) in the treatment of sickle cell disease in areas endemic for malaria, becauseit up-regulates the endothelial surface expression of ICAM-1, a major receptor for Plasmodium falciparum-infected erythrocytes in the brain. Using human in vitro models of cerebral malaria, we evaluated the interaction of HU with parasites and demonstrated that HU pretreatment increased the number of infected red blood cells adhering to the endothelium, but did not increase endothelial apoptosis. Moreover, using an experimental cerebral malaria model, HU pretreatment was found to prevent significantly mice from developing neurological syndrome by inhibiting parasite growth, opening potential therapeutic avenues.

Anemia, Sickle Cell↗

PubMed1984

Effects of hydroxyurea on concanavalin-A-induced T-cell proliferation. Depletion of T-cell growth factor-reactive and -producing T lymphocytes.

The effects of eliminating cycling precursors by in vivo administration of high doses of hydroxyurea (HU) in populations of mouse spleen T lymphocytes were studied by membrane immunofluorescence identifying mature Thy 1+, Lyt 2- and Lyt 2+ cell populations and mitogen-induced T-cell growth factor (TCGF) production or reactivity to TCGF. HU treatment results in a sharp decrease in the total number of T cells in mouse spleen, indicating that about 50% of peripheral splenic T lymphocytes have a short survival time in vivo. This depletion is more marked for Lyt 2+ cells than for Lyt 2- cells. The decay of TCGF-reactive spleen cells after drug administration is similar to that of the overall spleen T-cell population. Conversely, production of TCGF induced by concanavalin A is predominantly affected by HU treatment, indicating a shorter life span of the cell(s) involved in TCGF production.

Animals↗

PubMed2005

Synthesis and X-ray crystal structure study of the hydroxyurea and hydantoin derivatives of L-valine.

The novel hydroxyurea 5 derivative of L-valine was prepared by aminolysis of N-(1-benzotriazolecarbonyl)-L-valine cyclohexanemethylamide 4 with hydroxylamine. The corresponding hydantoin derivative 6 was synthesized by base catalyzed cyclization of the amide 4. The exact stereostructure of hydantoin derivative 6 has been determined by X-ray crystal structure analysis. The chiral atom of the hydantoin ring in 6 has S configuration what is in agreement with its configuration in the starting L-valine. The molecules of 6 are joined into infinite chains by N-H...O intermolecular hydrogen bond. The infinite chains are additionally linked by two C-H...O hydrogen bonds, thus forming two-dimensional network. The hydantoin derivative of L-valine 6 and its L-leucine analogue LH have similar packing arrangements, so they are homostructural.

Crystallography, X-Ray↗

PubMed1980

Hydroxyurea in the management of chronic urea-splitting urinary infections.

The aim in the management of struvite stones is to remove all of the stones and to treat urinary infection. The bacterial species which are known to cause struvite stones produce the enzyme urease, which increases urinary pH by splitting urea and consequently causes urinary supersaturation with respect to struvite and hydroxyapatite. The use of bacterial urease inhibitors with antibiotics is a new and interesting aid in the management of chronic urea-splitting infections. We describe our experience with the use of hydroxyurea in 15 patients with chronic urea-splitting infections.

Adolescent↗

PubMed1982

A pilot study of hydroxyurea in hormone "escaped" metastatic carcinoma of the prostate.

Twenty-two patients with metastatic carcinoma of the prostate no longer responsive to hormonal therapy with stilboestrol 1 mg tds have been studied in a Phase II clinical trial of hydroxyurea 80 mg/kg body weight every third day after discontinuing their hormonal therapy. There was a partial objective response in 22.7%, a stable state response in 13.6% and a subjective response in a further 31.8%. The patients who showed a response to treatment survived longer than those who did not show a response and with a better quality of life. The response rate was higher in patients who started treatment without significant delay after diagnosis of relapse. Metastatic disease responded better than the primary tumour. Side effects were not a significant problem.

Aged↗

PubMed2006

Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?

BACKGROUND: Polymorphonuclear leukocytes (PMN) from healthy subjects can produce and store tissue factor (TF), which is expressed on PMN surface upon in vitro stimulation with P-selectin. RESULTS: We report here that platelets and PMN from 12 patients with myeloproliferative disorders (MPD) (six with polycythemia vera, six with essential thrombocythemia) show up regulation of P-selectin and TF, respectively, in the absence of any in vitro challenge. The number of circulating mixed platelet-PMN aggregates was also increased. PMN TF expression as well as mixed platelet-PMN aggregates, but not platelet P-selectin, were significantly reduced in six MPD patients after treatment with hydroxyurea (HU). In vitro studies performed on PMN separated from healthy donors confirmed HU effects (0-1400 microm). HU prevented both P-selectin-induced TF expression and mixed cell aggregate formation. The inhibitory effect of HU was specific for P-selectin-induced PMN activation, as it did not affect formyl-methionyl-leucyl-phenylalanine-induced PMN TF expression. CONCLUSIONS: In MPD patients, platelet P-selectin-mediated TF expression on circulating PMN may play a role in thrombus formation and represents a novel target for the antithrombotic activity of HU.

Aged↗

PubMed1979

Effects of hydroxyurea on Crithidia fasciculata.

Hydroxyurea (HU) inhibits increase in cell number in cultures of Crithidia fasciculata. Complete inhibition is produced by 8 mM and higher concentrations. If HU is not removed, population growth resumes in 45-50 h; if HU is removed, partially synchronous growth occurs through 2 cycles. During HU inhibition, the rate of DNA synthesis is reduced to 1% of that in exponentially growing cultures; protein and RNA syntheses continue at slightly reduced rates. Mean cell size and protein and RNA contents per cell increase; rate of oxygen consumption per mg cell protein remains constant. The behavior of a culture upon addition of HU and upon its removal agrees with predictions based on the hypothesis that the only direct effect of HU is to block DNA synthesis. The synchrony produced by HU is judged satisfactory for investigations of kinetoplast and nuclear replication but not for biochemical characterization of other aspects of the cell cycle.

Animals↗

PubMed1980

Hydroxyurea: effect on growth, structure, and [3H]thymidine uptake of Trypanosoma brucei procyclic culture forms.

Hydroxyurea (HU) in concentrations above 50 micrograms/ml reversibly inhibited cell division of Trypanosoma brucei brucei stock STIB 336 procyclic culture forms, but not growth of individual cells. The volume of the nucleus and of the cytoplasm increased in the presence of the drug as did the percentage of cells with 2 kinetoplasts. Electron microscopy revealed that the nuclear membrane was extended forming protrusions which surrounded areas of the cytoplasm. Replication of the kinetoplast DNA did not seem to be affected by HU. The uptake of [3H]thymidine increased in the presence of 25 micrograms/ml HU 3-fold compared to control cells. The nuclear volume and the dry weight of the culture forms increased proportionally to the amount of label incorporated.

Animals↗

PubMed1985

Amelioration of hydroxyurea-induced suppression of phagocytosis in human granulocytes by free radical scavengers.

The exposure of human circulatory white cells in vitro to 0.1-1-10 mol/l hydroxyurea (HU) for 20 h induced a progressive dose-dependent suppression of the phagocytic activity of granulocytes. The suppressing effect of 20 h exposure to 1 mol/l HU was used to examine the protection afforded by free radical scavengers against HU-induced cytotoxicity. It has been found that, in the suitable concentration of the protecting agent, a substantial protective effect of sodium benzoate, acetylosalicylic acid, alpha-tocopherol, ascorbic acid, catalase, peroxidase or superoxide dismutase can be achieved.

Antioxidants↗