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PubMed1990

Hypoxanthine enhances hydroxyurea-induced sister-chromatid exchanges in Chinese hamster ovary cells.

Treatment with 1 mM hydroxyurea (HU) for 12 h induced sister-chromatid exchange (SCE) in CHO-K1 cells. The induced SCE frequency was always higher in cells grown in Ham's F12 medium than in those grown in RPMI 1640 medium. It was shown that hypoxanthine (Hyp), a component of Ham's F12, was to a great extent responsible for producing a higher level of HU-induced SCEs: HU-induced SCEs were synergistically enhanced when Hyp was added to RPMI 1640 medium supplemented with dialyzed fetal bovine serum at a concentration of 30 microM, which is the concentration in Ham's F12 medium. The radioactivity of [14C]Hyp was readily incorporated into DNA in either the presence or the absence of HU. The greater part was in the forms of dGMP and dAMP. It was not clear whether Hyp was incorporated in the form of dIMP or not. Deoxyguanosine (dGuo), but not deoxyadenosine (dAdo) reversed both the incorporation of radioactivity into DNA and the SCE-enhancing effect of Hyp. Our results indicate that incorporation of Hyp into the dNTP pools and into the DNA, together with perturbation of dGuo metabolism under abnormal conditions during and after HU treatment, is involved in the enhancement by Hyp of HU-induced SCEs.

Animals↗

PubMed1994

The induction of chromosomal damage and cell killing in mouse spermatogonial stem cells following combined treatments with hydroxyurea, 3-aminobenzamide and X-rays.

To analyze in more detail the relation between the sensitivity of spermatogonial stem cells to killing and the induction of genetic damage, mature male mice received combined treatments with hydroxyurea (HU), 3-amino-benzamide (3-AB) and X-rays. Stem cell killing was determined using the repopulation index method and translocations were studied via spermatocyte analysis. HU was administered at 16 or at 48 h before further treatment in order to create stem cell populations with different sensitivities in which the translocation induction and stem cell killing could be studied and compared. The sensitivities for cell death and genetic damage appeared to be strongly correlated: at 16 h after HU significantly higher values were found than at 48 h or in controls without HU pretreatment. By using 3-AB in the treatment schedules we were able to investigate whether the sensitization of stem cells towards cell death and genetic damage is the outcome of a radiation- or drug-induced G1 delay. The effect of 3-AB was most pronounced at 16 h after HU. This confirms that at this interval a large fraction of stem cells is in G1. Our data therefore indicate that all treatments that induce an enrichment of G1 cells also result in a sensitization of stem cells to cell killing or the induction of mutagenic damage.

Animals↗

PubMed1996

Effect of hydroxyurea and normal plasma on DNA synthesis in lymphocytes from Fanconi anemia patients.

Fanconi anemia (FA) is characterized at the cellular level by a high frequency of spontaneous chromosomal aberrations; crosslinking agents cause an abnormal increase in the frequency of chromosomal damage, and semiconservative DNA synthesis is severely inhibited. Deoxyribonucleotides are needed in both semiconservative and repair DNA synthesis. To investigate the involvement of deoxyribonucleotide pools in the inhibition of DNA synthesis in FA, we evaluated the effect on FA lymphocytes of hydroxyurea (HU), an inhibitor of ribonucleotide reductase which is known to alter the intracellular levels of deoxyribonucleotides. To achieve this goal, lymphocyte cultures of 4 FA patients and 4 normal individuals were used. Cultures were treated with HU and/or mitomycin C and normal human plasma. All cultures were processed to detect the number of DNA synthesizing nuclei by autoradiography. Scoring of 2000 nuclei for each kind of culture every 6 h in the last 24 h of incubation showed that, in long incubation periods, DNA synthesis in FA is largely inhibited by HU and this hypersensitivity may be partially decreased by addition of normal human plasma. It is known that recovery from damage induced by HU involves several enzymes such as flavin oxido-reductase, superoxide dismutase and catalase which are involved in the production or scavenging of O2 radicals; FA cells are deficient in the detoxification of oxygen and this could explain the response of FA cells to HU.

Cells, Cultured↗

PubMed1986

Potentiation of hydroxyurea cytotoxicity in human chronic myeloid leukemia cells by iron-chelating agent.

The effect of hydroxyurea (HU) was studied in 15 cases of human chronic myeloid leukemia cells (CML) in combination with iron-chelating agent, 2,2-bipyridine (bipyridine). The extent of (3H)thymidine incorporation in CML cells in vitro was taken as an index for the measurement of cytotoxicity. In the present study, we observed a potentiation in HU cytotoxicity by hydrophobic iron-chelator bipyridine (p less than 0.001) resulting in complete DNA biosynthesis inhibition. Both HU and bipyridine were used at a relatively non-toxic concentrations of 10(-4) M and 10 micrograms/ml, respectively. This inhibition was found to be partially reversible and a partial protective action by iron is also demonstrated. The various other metal chelators failed to sensitise CML cells to HU cytotoxicity. Implications with respect to the efficacy in cancer treatment is discussed.

2,2'-Dipyridyl↗

PubMed1975

Hydroxyurea.

Hydroxyurea (HU) is an anti-leukaemia and anti-tumour drug which has also found limited application in the treatment of dermatological disorders. It is a potent inhibitor of DNA synthesis in many organisms from viruses to man and in cell culture systems. To a lesser degree it can also inhibit RNA and protein synthesis. It is anti-mitotic and cytotoxic depending on the concentration used, the duration of exposure, and the sensitivity of the organism. In most cells HU is active mainly in the S-phase of the cycle and because of the easy reversibility of its action it has been used as a synchronising agent in cell cultures with some success. There is conflicting evidence about the ability of HU to act as an inhibitor of the natural DNA repair mechanisms in cells exposed to radiation or alkylating agents. HU has, however, been shown to induce chromosome damage in a number of organisms including man. It is clearly teratogenic in mammals and can cross the placental barrier at least in rats and the golden hamster, but it is believed to have only a limited mutagenic activity. Studies involving a direct comparison of the action of HU with other compounds suggest that the = C--NHOH moiety is responsible for its biological activity.

Animals↗

PubMed1987

Comparison of the continuous rat hepatoma cell line 2sFou with primary rat hepatocyte cultures for the induction of DNA repair synthesis by nitrosamines, benzo[a]pyrene and hydroxyurea.

We have examined the suitability of the continuous rat hepatoma cell line 2sFou for testing the genotoxicity of chemicals in comparison with that of primary rat hepatocyte cultures (HPC). The capacity of the cells for metabolic activation was assessed by measuring induction of DNA-repair synthesis and inhibition of replicative DNA synthesis by the test compounds dimethylnitrosamine (DMN), diethylnitrosamine (DEN), hydroxyurea (HU) and benzo[a]pyrene (BaP), which are substrates for major hepatic and extrahepatic forms of cytochrome P-450 dependent monooxygenases. The cellular capacity for DNA-repair synthesis was assessed using UV-light as a DNA-damaging agent. Repair-specific incorporation of [3H]deoxycytidine (3H-dCyd) caused by UV-light was higher in 2sFou cells than in HPC. In contrast, background repair incorporation of 3H-dCyd in 2sFou cells was only 1/3 that found in HPC. All the test agents induced DNA repair and inhibited DNA synthesis in both 2sFou cells and HPC. The two nitrosamines were more effective in HPC than in 2sFou cells. HU and BaP affected DNA repair and DNA synthesis in the two cell systems at a similar range of concentrations. In general, DNA repair in the 2sFou cells increased near linearly with the concentrations of the test compounds. The data indicate that 2sFou cells are capable of activating hepatotropic pro-mutagens/carcinogens such as dialkylnitrosamines, and are sensitive indicators of DNA damage. In contrast, BaP, a non-hepatotoxic compound, caused only little DNA repair in these cells. Thus, continuously growing cells, such as 2sFou, show a qualitatively similar response to genotoxic chemicals as HPC and offer a potential alternative to HPC for genotoxicity testing.

Animals↗

PubMed1987

Effect of hydroxyurea on the concanavalin-A proliferative response of Trypanosoma cruzi infected mice.

Mice infected with Trypanosoma cruzi develop immunosuppression with a deficient production of interleukin-2 (IL-2). In this situation the deficient concanavalin A (Con A) T-cell response is not corrected by addition of exogenous IL-2. Here we show that elimination of cycling cells by treatment of infected mice with hydroxyurea (HU) fully restored the ability of spleen cells to respond to IL-2. Further, capacity for IL-2 production was restored to HU treated infected mice, but not as completely as the response to IL-2.

Animals↗

PubMed1990

The relation between induced reciprocal translocations and cell killing of mouse spermatogonial stem cells after combined treatments with hydroxyurea and X-rays.

The induction of reciprocal translocations in mouse spermatogonial stem cells, visualised in dividing primary spermatocytes, was studied after combined treatments with hydroxyurea (250 and 500 mg/kg) and X-rays (6, 8 and 9 Gy). The time intervals between the 2 treatments were 16 h (leading to extremely high cell killing) and 48 h (giving rise to less killing than irradiation alone). Comparison of the observed frequencies of translocations with reported data on stem cell killing (de Ruiter-Bootsma and Davids, 1981) show that the ratio between the probabilities that a radiation-induced basic lesion kills a cell or produces a translocation, theoretically calculated by Leenhouts and Chadwick (1981) to be about 10, can indeed be confirmed experimentally.

Animals↗

PubMed1996

Effects of aphidicolin and hydroxyurea on the cell cycle and differentiation of Trypanosoma brucei bloodstream forms.

The effects of aphidicolin (APH) and hydroxyurea (HU) on the cell cycle and differentiation of Trypanosoma brucei bloodstream forms were studied. APH (0.1 microgram ml-1) inhibited cell division, but did not inhibit DNA synthesis. Most of the cells were arrested in the G2 phase of the cell cycle, with each cell containing two kinetoplasts, but only one nucleus. Recovery of the arrested cells showed a 24-h lag period compared to controls. Higher concentrations of APH (1 and 10 micrograms ml-1) were required to inhibit DNA synthesis, but the cells failed to resume growth after removal of the drug. Incubation of cells with HU (7.5 micrograms ml-1) did not inhibit DNA synthesis, but arrested cells after duplicating both the kinetoplast and the nucleus. Recovery from drug arrest also showed a 24-h lag period. We therefore conclude that neither APH nor HU arrests T. brucei at the G1/S phase boundary as anticipated. The mechanisms of cell cycle arrest by APH and HU are not through inhibition of DNA synthesis, but rather through unidentified pathways, leading to growth arrest prior to nuclear division and cytokinesis respectively. Since the arrested cells do not resume normal development immediately following drug removal, APH and HU should be regarded as unsuitable agents for synchronizing T. brucei bloodstream forms. T. brucei bloodstream forms arrested with either APH or HU differentiated normally into procyclic forms in vitro, indicating that a cycle of cell division is not required for initiation of differentiation, and that the process can be initiated and completed when cells are arrested at the G2/M and M/G1 phase boundaries.

Animals↗

PubMed1995

Regulation of c-jun mRNA expression by hydroxyurea in human K562 cells during erythroid differentiation.

Hydroxyurea (HU) is an antitumor agent which also induces hemoglobinization during erythroid differentiation. In addition, HU stimulates the synthesis of fetal hemoglobin in sickle cell anemia patients. To further understand its mechanism of action, we investigated the effects of HU on regulation of c-jun expression prior to the onset of erythroid differentiation of K562 cells. HU induced a dose-dependent stimulation of c-jun synthesis. The levels of c-jun mRNA was elevated 4 to 7.5-fold by HU within 2 h. This was followed by a gradual decline to the basal level by 24 h. Both nuclear run-on and actinomycin D pulse experiments strongly indicate that HU regulates c-jun mRNA expression by increasing the rate of synthesis as well as stabilizing the c-jun mRNA. In addition, the level of jun protein was elevated by 2 to 5-fold within 4 h in HU treated cells. Furthermore, concentrations of HU below 250 microM slightly increased the 5X AP-1/CAT activity. These results strongly suggest that HU induces both transcriptional and post-transcription regulation of c-jun during erythroid differentiation.

Cell Differentiation↗

PubMed1992

Hydroxyurea induces apoptosis and regular DNA fragmentation in a Burkitt's lymphoma cell line.

Hydroxyurea (HU) is an S-phase-specific cytotoxic drug used in the clinical treatment of haematological malignancies. HU treatment has been shown to lead to accumulation of short DNA fragments which show direct correlation with cytotoxicity. Specific regular DNA fragmentation is a biochemical feature of apoptosis (programmed cell death) in some systems. We investigated the effect of HU on a neoplastic (Burkitt's lymphoma) cell line (BM13674) in vitro to determine the role of apoptosis in HU action. HU produced growth inhibition and cell death by apoptosis in BM13674 cells. Low dose HU (66 and 131 mumol/l) gave a growth inhibition effect only with no apoptosis being induced. Higher doses (0.66-13 mmol/l) induced apoptosis in a dose-dependent manner. Regular DNA fragmentation was detected by agarose gel electrophoresis of DNA and this correlated in time with the onset of apoptosis detected by light and electron microscopy. The results do not exclude the possibility that HU directly induces DNA strand breaks, which then initiate apoptosis and accompanying regular fragmentation of DNA in the apoptotic cells.

Burkitt Lymphoma↗

PubMedDate not supplied

The role of deoxynucleoside triphosphate pools in the inhibition of DNA-excision repair and replication in human cells by hydroxyurea.

The effects of hydroxyurea (HU) on the DNA-excision repair process in human cells has been systematically examined. It is demonstrated that HU induces DNA single-strand break accumulation in a dose-dependent fashion in ultraviolet-irradiated and MMS-treated confluent but not log-phase fibroblasts and that these breaks are clearly the consequence of the inhibition by HU of the enzyme, ribonucleotide reductase. The breaks form rapidly, are stable for at least 10 h and largely disappear by 20 h. The production of these DNA-strand breaks is antagonized by a combined treatment of 10 microM deoxyadenosine, deoxycytidine and deoxyguanosine whereas thymidine potentiates strand-break formation at low HU concentrations. It is also confirmed that HU, while inhibiting replicative synthesis has no apparent inhibitory effect on unscheduled DNA synthesis (UDS) although the increased uptake of labeled DNA precursors into HU-treated cells makes it difficult to assess the actual effects on the repair-synthetic process. Analysis of the effects of HU on deoxynucleoside triphosphate pool levels and the demonstration of the failure of the HU block to replicative synthesis to be reversed by high (1 mM) concentrations of added deoxynucleosides lend support to the notion of compartmentalized dNTP pools for repair and replication.

Cells, Cultured↗

PubMed1985

The teratogenic interaction of hydroxyurea and 5-bromodeoxyuridine examined with the aid of limb culture and image analysis.

Pregnant mice were treated on gestation Day 11 (E11) with a single dose of either hydroxyurea (HU, 250 mg/kg) or 5-bromo-2'deoxyuridine (BrdU, 500 mg/kg), or with a combination of the two agents. The dams were either allowed to go to term, when the fetuses were examined for cleft palate (CP) and digital anomalies, or killed 24 hr after the treatment. In the latter case, limbs from the embryos of control and treated dams were excised and cultured for 6 days in submerged culture. At the end of the culture period, the limb explants were stained for cartilage. The various cartilaginous components were subsequently analyzed using image analysis methods. CP was observed in 2.4 and 22.9% of the fetuses, respectively, after a single dose of HU or BrdU on E11. Simultaneous HU + BrdU treatment decreased the incidence of BrdU-induced CP to 3.6%, while treatment with BrdU 3 hr after HU resulted in 33.3% CP. In addition, syndactyly and ectrodactyly, not seen after the treatment with either HU or BrdU alone, were observed when the two agents were administered simultaneously, 1 hr apart or with a 3-hr delay. The teratogenic response was enhanced when limbs were cultured for 6 days. Digital anomalies were observed in the limb explants of BrdU-pretreated embryos; such abnormalities were not observed in vivo. Image analysis of cultured limb explants revealed that with HU-3 hr-BrdU pretreatment, the total limb area occupied by the long bones was increased at the cost of the paw area. However, no consistent changes in the shape or form of individual bones were observed. HU and BrdU given together produced a teratogenic response which was significantly different from that observed following the administration of HU or BrdU alone. This is considered to be due to an interference with the incorporation of BrdU in the DNA, since HU is known to block DNA synthesis. When HU was given before BrdU, the effects of BrdU were enhanced, probably due to the reported synchronizing action of HU on dividing cells. We also found that after a similar in utero exposure, the culture conditions themselves enhanced the frequency of teratogenic expression of BrdU.

Abnormalities, Drug-Induced↗

PubMed1986

Phase II study of a combination of hydroxyurea, fluorouracil and mitomycin in previously treated squamous cell carcinoma of the head and neck.

Thirty-six evaluable patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck were treated with a combination of mitomycin (10 mg/m2 i.v. day 1), fluorouracil (500 mg/m2 i.v. days 1 + 8) and hydroxyurea (1 g/m2 orally days 2-14). Thirty-three patients had received prior radiation therapy and 34 prior chemotherapy. Only two patients exhibited a partial response. Hematological toxicity was substantial, with three patients experiencing leukopenia below 1000/mm3 and seven patients experiencing thrombocytopenia below 25,000/mm3. There were four cases of treatment-related bleeding and one infection. Other side-effects were mild to moderate. Low antitumor activity and substantial toxicity preclude further evaluation of this regimen in head and neck cancer.

Adult↗

PubMedDate not supplied

Protection against hydroxyurea-induced cytotoxic effects in L5178Y cells by free radical scavengers.

Exposure of L5178Y cells in culture to 1 mM hydroxyurea (HU) for 3 h followed by 24 h incubation in an HU-free medium induced an abnormal enlargement of about 40% of the cells in the population and post-treatment reduction of DNA synthesis in comparison with control cells. These effects were used to examine the protection afforded by free radical scavengers against HU-induced cytotoxicity. It has been found that with careful choice of conditions (suitable concentration of the protective agent, pretreatment of cells) substantial protective effect of alpha-tocopherol, sodium benzoate, acetylsalicylic acid, catalase, peroxidase or superoxide dismutase can be achieved.

Animals↗

PubMed1984

Effects of hydroxyurea consistent with the inhibition of repair synthesis in ultraviolet irradiated HeLa cells.

Many studies on DNA repair using established in vitro cell cultures employ conditions of low serum, nutrient deprivation, and blockade with hydroxyurea (HU) to reduce the background levels of DNA replication. There are some reports in the literature which indicate that HU inhibits DNA repair. In the present study the effects of HU on strand breaks and repair synthesis in UV irradiated Hela cells were investigated using a combined strand break and UDS assay. In conditions of low serum and arginine deprivation, HU produced effects consistent with the inhibition of the repair synthesis step in excision repair. Although the conditions used in this study are severe the results suggest that HU may have qualitatively similar effects in other studies which employ its use to detect repair synthesis.

DNA↗

PubMed1992

Synergistic inhibition of human gastric carcinoma cell growth by 1-beta-D-arabinofuranosylcytosine and hydroxyurea or 2'-deoxyguanosine in vitro.

The cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) in combination with hydroxyurea (HU) or 2'-deoxyguanosine (GdR) on human gastric carcinoma MK-1 cells and colon carcinoma HT-15 cells was studied. Synergistic interaction between ara-C and HU on MK-1 cells and HT-15 cells, or ara-C and GdR on MK-1 cells was shown using the combination index method. HU increased the accumulation of ara-C triphosphate (ara-CTP) in the acid-soluble pool and diminished the cellular deoxyCTP (dCTP) pool. HU had no effect on the incorporation of ara-C into DNA and RNA. These results indicate that HU-induced elevation in ara-CTP and decrease in dCTP are the basis for synergy among ara-C and HU in MK-1 cells. GdR diminished cellular dCTP slightly, but it decreased the accumulation of ara-CTP in the acid-soluble pool and did not increase the incorporation of ara-C into DNA. On the other hand, ara-C increased cellular deoxyGTP (dGTP) level in the presence of GdR. These results indicate that synergy between ara-C and GdR is mediated through increased cellular dGTP which might inhibit DNA synthesis directly.

Carcinoma↗

PubMed1989

Deoxyribonucleoside triphosphate pools in regenerating rat liver: effect of hydroxyurea and exogenous deoxypyrimidines.

Hydroxyurea (HU) causes inhibition of DNA synthesis in regenerating rat liver due to an inhibition of the ribonucleotide reductase. We studied the consequences of a continuous HU infusion for deoxyribonucleoside triphosphate (dNTP) pools in the liver after partial hepatectomy and tried to modify imbalances by application of deoxyribonucleosides in vivo. In normal liver, an intracellular concentration of 0.16, 0.84, 0.33 and 0.27 pmol/micrograms DNA was observed for dATP, dCTP, dGTP and dTTP, respectively. In regenerating liver the dNTP pools show minor changes until 18 h after partial hepatectomy. During and after a continuous HU infusion 14--24 h after partial hepatectomy, the intracellular dNTP pools change considerably. At 19.5 h after partial hepatectomy, 5.5 h after the start of HU infusion, and at 25 h after partial hepatectomy, 1 h after termination of HU infusion, the dTTP pool was more than 10-times, and the dGTP pool about 2-times higher than in controls, while the dATP and dCTP pools remain relatively unchanged. Simultaneous infusion of HU and deoxythymidine (dThd) 14--25 h after partial hepatectomy results in a further increase of the dTTP pool during and after HU infusion. Administration of deoxycytidine (dCyd) leads to a moderate increase of the dCTP pool and a weak decrease of the dTTP pool during HU infusion. The combined application of dCyd and dThd after HU infusion had similar effects on dNTP pools as observed with dThd alone. These results show that intracellular pools of dNTPs in hepatocytes can be altered by exogenous factors in a controlled pattern. This system can be used as a model for studying the implications of induced dNTP pool dysbalances for the initiation of liver carcinogenesis by mutagenic chemicals.

Animals↗