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PubMed1985

Flow cytometric analysis of hepatoma tissue and HeLa cells grown on various types of microbeads using hydroxyurea, nocodazole and aphidicolin in succession.

Applying Hydroxyurea, Nocodazole and Aphidicolin in succession to obtain parasynchronous growth, the progression of HTC and HeLa cells through the cell cycle has been monitored by laser flow cytometry. The experimental results show that HTC cells behave identically whether grown in monolayer or attached to dextran-based microbeads but that the chemical nature of the micro-support itself plays an important role especially on the speed with which the cells pass from mitosis into G1, polyacrylamide-based microbeads being superior in this respect.

Aphidicolin↗

PubMed1986

Phase II study of combined carmustine, 5-fluorouracil, hydroxyurea, and 6-mercaptopurine (BFHM) for the treatment of malignant gliomas.

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Adolescent↗

PubMed1988

[The resonance nature of the dependence of epithelial lesions of the small intestine in mice on the interval between injections of an S-phase-specific agent--hydroxyurea].

The dependence of the injury of murine small intestinal epithelium on the interval between multiple regular injections of hydroxyurea (HU) was investigated. Mice were injected 8 times with HU (5 mg per injection) in different experimental groups of animals, and the interval between injections varied from 6 to 19 hours. With the intervals between the injections close to 8 or 16.5 hours the resonance decrease of the injury was observed whereas the intervals of 6, 12 and 19 hours corresponded to maximum injury.

Animals↗

PubMedDate not supplied

[Cytogenetic effect of irradiation and subsequent cytosine arabinoside and hydroxyurea treatment on Chinese hamster cells in the G1 phase of the cell cycle].

A two-hour treatment of Chinese hamster cells at the G1 stage of the cell cycle with arabinoside cytosine combined with hydroxyurea after X-irradiation (50-300 cGy) produced a 2- to 4-fold increase in the frequency of chromosome aberrations. The mitotic selection method was used to synchronize the cells. The potentiating effect of the inhibitors, that was estimated by the yield of centric exchanges, decreased with increasing radiation dose. It is suggested that DNA repair processes determining a linear component of the dose-response curve are modified within the dose-range under study.

Animals↗

PubMed1987

Influence of hydroxyurea on lectin-induced early and late events in peripheral blood lymphocyte cultures.

Activation events induced by lectins in human lymphocyte cultures differed not only in time kinetics of their appearance but were also in a different manner inhibited by hydroxyurea (HU). 4F2 and Tac expression, thermostable sheep erythrocyte rosette formation, cell volume distribution changes and the enhancement of the purine metabolic rate [( 3H]adenine incorporation) induced by PHA, Con A or PWM were not influenced by HU treatment, suggesting G1-phase dependency of these markers. The decrease in the mitogen-induced marker expression after 48 h of incubation with HU can be explained by the unability of activated cells to process the cell cycle, to divide and to become newly positive cells. Mitogen-induced RNA synthesis was partially, DNA synthesis, PWM-induced Ig synthesis and lectin-mediated HLA class II antigen expression were totally inhibited by HU. It holds especially for the DR antigen that its appearance in a polyclonal model of lymphocyte activation occurs in a later (postmitotic G1) phase of the cell cycle. The inhibitory effect of HU on late activation parameters could be removed after washing the cells. Mitogen-activated, HU-treated PBL cultures after removing HU continued cell cycle progression without requirement for further addition of lectin.

Adenine↗

PubMedDate not supplied

Sensitization of P388 murine leukemia cells to hydroxyurea cytotoxicity by hydrophobic iron-chelating agents.

The potentiation in the cytotoxic effect of antineoplastic agent hydroxyurea (HU) from the non-toxic concentration on P388 murine lymphocytic leukemia cells is observed with the hydrophobic iron-chelating agents, 2,2-bipyridine (bipyridyl) and 1,10-phenanthroline in a concentration and time dependent manner. However EDTA, EGTA, 2,3-dihydroxybenzoic acid (2,3-DBA), Rhodotorulic acid, 8-hydroxyquinoline (8-Hq), catechin and Desferal, and other chelators failed to show sensitization of these tumor cells towards HU. The potentiation in the cytotoxic activity of HU in combination with the bipyridyl was found to be reversible but was maintained when the drug exposed cells were washed and retreated with the non-toxic concentrations of HU or bipyridyl. The presence of Fe++ blocked completely the cytotoxic action of HU alone and a combination with iron-chelator, and partially reversed the inhibition induced by HU and bipyridyl. These findings suggest that the hydrophobic iron-chelators affect the membrane-mediated transfer, localisation and transient intracellular chelatable iron pools. As a consequence of this, the regulatory role mediated by iron on the overall activity of ribonucleotide reductase enzyme is disturbed leading to a conclusive imbalance in DNA biosynthesis.

2,2'-Dipyridyl↗

PubMed1987

Progressive formation of DNA lesions in cultured Ehrlich ascites tumor cells treated with hydroxyurea.

We have previously demonstrated an accumulation of strand breaks in mature DNA of cultured Ehrlich ascites tumor cells treated with methotrexate. We postulated that the strand breaks arose from unrepaired spontaneous DNA lesions. The present study describes a progressive accumulation of strand breaks in mature DNA of Ehrlich ascites cells treated with hydroxyurea (HU). Strand breaks were determined by alkaline elution. Accumulation of strand breaks was dependent on the length of incubation (0-16 h) and on HU concentration (0-10 mM). About 70% of strand breaks were repaired when cells were incubated without HU. About 67% of strand breaks were prevented by 0.4 mM deoxyadenosine, deoxyguanosine, and deoxycytidine, with or without thymidine. Prevention was less effective by deoxyadenosine and deoxyguanosine and ineffective by deoxycytidine. Free radical scavengers did not prevent strand breaks. S-phase cells accumulated about twice the number of strand breaks as non-S-phase cells. Cell survival decreased in proportion to the increase in HU concentration (0-10 mM). The results demonstrate that lack of purine, as well as of pyrimidine, nucleotides results in strand breaks in mature DNA, suggest that HU cytotoxicity is due to fragmentation of mature DNA, and caution against the use of HU in DNA repair studies.

Animals↗

PubMed1987

Modification by caffeine of acute cytotoxic response of cultured L5178Y cells to hydroxyurea treatment.

The effect of caffeine (CAF) on acute cytotoxic response of L5178Y lymphoblasts to hydroxyurea (HU) treatment was studied. The following events were examined: abnormal cell enlargement (giant cell formation), the rate of recovery of cell reproduction and DNA synthesis after releasing the cells from the HU blockage, parental DNA breakage and cell death. The presence of CAF at nontoxic concentration prevented giant cell formation, enhanced cell growth inhibition and cell killing. The effect of CAF was variable, dependent on the duration of exposure to HU and the time of exposure to CAF. To obtain maximal effect, the continuous presence of CAF during HU treatment and posttreatment time was necessary. Hydroxyapatite chromatography assay of single strand (ss) and double strand (ds) fractions in parental DNA and the measurement of the rate of post-treatment recovery of DNA synthesis indicated that CAF enhanced HU-induced DNA lesions. It is concluded that the results give further evidence that even short HU treatment can damage not only newly formed but also parental DNA. The lesions are normally, at least partly repaired and can be expressed under the conditions of DNA repair inhibition.

Animals↗

PubMed1987

[Significance of the intervals of hydroxyurea administration for epithelial damage to the small intestine in mice].

The states of the murine small intestinal epithelium 6, 30 and 78 h after the end of the multiple regular injections of hydroxyurea (HU) were analysed with the aid of the light and electron microscopy. The course of 6 regular injections of 5 mg/mouse HU was begun 24 h after the initiating gamma-irradiation in a dose 200 rad and the interval between injections was varied from 7 to 19 h for different experimental groups of mice. The analysis of the epithelial state revealed two minima of the tissue damage which correspond to the courses of HU injections with the intervals close 9 h and 16.5 h.

Animals↗

PubMed1986

Cross-sensitivity of methylating agents, hydroxyurea, and methotrexate in human tumor cells of the Mer- phenotype.

Five human tumor cell lines of the Mer- phenotype sensitive to killing by the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide were sensitive to hydroxyurea (HU) compared with 15 cell lines resistant to methylating agents (Mer+ phenotype). In a study using fewer cell lines, Mer- cells were also sensitive to methotrexate but not to seven other agents including the antimetabolites 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil. Cells sensitive to HU were designated the Hu- phenotype. Five autologous Mer+ lines, derived in vitro by treating Mer- lines with methylating agents, did not become resistant to HU or methotrexate (Mer+ Hu- phenotype). All Mer+ lines studied had enhanced ability to reactive methylated adenovirus. Adenovirus was inactivated by prolonged treatment with HU, but no enhanced reactivation of HU-treated virus was found in Mer+ cell lines. Cell survival after 5-(3-methyl-1-triazeno)imidazole-4-carboxamide treatment was not significantly decreased by HU, nor was replication of methylated adenovirus inhibited by HU in Mer- or Mer+ lines. Replication of untreated adenovirus was poor in Mer- cells treated with HU, indicating that sensitivity of cells to HU was associated with inhibition of DNA synthesis. These results suggest that cell sensitivity to deoxynucleotide depletion is linked, perhaps coincidentally, to the Mer- phenotype. The retention of HU and methotrexate sensitivity by cells after development of resistance to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide may have therapeutic implications.

Adenoviridae↗

PubMed1986

[Resonance nature of the relation of mouse survival to the interval between administrations of the S-specific agent--hydroxyurea].

The dependence of murine survival on the intervals between periodic hydroxyurea (HU) injections was studied. The single dose of HU comprised 250 mg per kg. Intervals between injections varied from 5 to 19 hours while their number changed from 6 to 9 in different experiments. A resonant increase in the survival was observed under HU administered every 8-9 or 16 1/2 hours.

Animals↗

PubMed1985

Mechanism of synergistic cell killing by hydroxyurea and cytosine arabinoside.

Synergistic cell killing of human lymphoblastic leukemia cell line, CCRF-CEM, occurred when hydroxyurea (HU) was administered before 1-beta-D-arabinofuranosylcytosine (ara-C). At the optimal dose of HU (1mM), the ara-CTP concentration increased 4-fold and the intracellular accumulation of ara-C increased 4-fold, while the dCTP concentration decreased by more than 50%. Increased intracellular accumulation of ara-C after HU treatment was also observed in human acute myelogenous leukemic cells in circulating blood. Therefore, the synergistic cell kill of HU and ara-C may be the consequence of greater inhibition of DNA polymerase by the increased level of ara-CTP in the presence of the decreased concentration of the natural substrate of this enzyme, dCTP. This synergism was not due to an increased incorporation of ara-C into DNA since the treatment of cells with HU did not enhance the ara-C incorporation into DNA but rather suppressed it.

Biological Transport↗

PubMed1985

DNA metabolism during infection of Anacystis nidulans by cyanophage AS-1. VI. Effect of hydroxyurea and nalidixic acid on the development of cyanophage AS-1.

The use of the DNA inhibitors hydroxyurea (HU) and nalidixic acid (NAL) to elucidate patterns of DNA metabolism in AS-1 infected A. nidulans have led to several conclusions. First, HU and NAL at concentrations of 500 and 100 micrograms/ml, respectively, inhibited DNA synthesis in synchronized A. nidulans. Protein and chlorophyll synthesis remained essentially unchanged as did turbidity increases. Second, the complete burst size of the cyanophage AS-1 was severely affected by HU and NAL treatment and burst sizes of 8 and 2.6, respectively, were obtained. Third, inhibitor treatment of infected cultures caused a premature release of phage at 12 h instead of 16 h post infection. Finally, HU treatment of the host cell had no effect on the formation of PIL-DNA, whereas NAL pretreatment blocked its formation.

Chlorophyll↗

PubMed1986

Effect of hydroxyurea treatment on lysosomal membrane stability and enzyme latency in L5178Y cells in culture.

The stability of lysosomes prepared from hydroxyurea (HU) treated or untreated L5178Y cells and exposed to an HU-free iso- or hypoosmotic solution was compared. The data revealed that exposure of the cells to 1-10 mM HU for few hours tends to stabilize lysosomes. Partial protection against this effect could be afforded by catalase and superoxide dismutase. Under the same conditions of HU treatment lysosomal enzyme latency remained similar in HU treated and untreated cells.

Acid Phosphatase↗

PubMed1985

Factors modifying cytotoxicity induced by 5-FU and hydroxyurea.

Pretreatment of exponentially growing 9L cells for 24 hours with a nontoxic (0.77 microM) or moderately toxic (7.7 microM) concentration of 5-FU (5-FUra) enhanced cell kill induced by a subsequent 6-hour treatment with 1.3 mM hydroxyurea (HU) by a magnitude of 1 log. In confluent 9L cultures or 9L cells treated in serum-free medium that decreased the cycling population, however, the 5-FUra-HU combination did not enhance the cell kill. No recovery from potentially lethal damage was observed for up to 24 hours after treatment of 9L cells with 7.7 microM 5-FUra alone or with 0.77 or 7.7 microM 5-FUra followed by 1.3 mM HU. These results show that 5-FUra and HU in combination kill cycling cells effectively and that cytotoxicity is fixed on completion of the treatment. Although the number of sister chromatid exchanges per metaphase increased significantly with increasing length of exposure to a nontoxic (0.77 microM) or moderately toxic (7.7 microM) concentration of 5-FUra, subsequent treatment with HU that resulted in cell kills of 70%-80% and 99%, respectively, did not increase the number of sister chromatid exchanges per metaphase beyond that expected from 5-FUra treatment alone. Thus, the enhanced cell kill does not appear to be a result of direct DNA damage.

Animals↗

PubMed1979

The suicide technique in vitro for granulocytic progenitor cells (CFC) by application of hydroxyurea (HU) to low concentrations of human bone marrow cells.

A suicide technique applicable to human bone marrow granulocytic progenitor cells has been previously described (3). This study discusses the conditions for its use on bone marrow aspirates poor in cells. When the number of cells exposed to hydroxyurea (HU) is proportional to the quantity of HU it is possible to avoid artifacts due to HU toxicity. This technique can repeatedly reproduce a 40--50% suicide. To obtain this result we suggest using a 6.10(-6) mM/ml/cell HU concentration.

Bone Marrow↗

PubMed1979

Hydroxyurea suicide study of the kinetic heterogeneity of colony forming cells in human bone marrow.

The kinetics of granulomonocyte colony forming cells have been studied in unfractionated normal human bone marrow by hydroxyurea suicide and in cells separated by velocity sedimentation. Sequential studies revealed two subpopulations of colony forming cells, having different sizes and different multiplication potentialities. There are large cells with a high suicide rate which develop small granulocyte and monocyte colonies during the first week of culture in semi-solid agar. Smaller cells develop larger colonies of granulocytes, monocytes and eosinophils between 2 and 3 weeks of culture. Only granulocyte progenitors have a substantial suicide rate in this small cell population. This population is also less responsive to stimulation than is the large cell class, which is a more highly differentiated progeny. The role of these different kinetics of colony forming cells is discussed in the context of the heterogeneity of the in vitro differentiation of neutrophil, monocyte and eosinophil lines.

Bone Marrow Cells↗

PubMed1979

In vivo cell cycle synchronization of the murine sarcoma 180 tumor following alternating periods of hydroxyurea blockade and release.

The durations of the cell cycle intervals of the murine Sarcoma 180 tumor were determined by computer analysis of the fraction-labeled mitosis curve following tritiated thymidine administration. This tumor has a usual total cell cycle duration of 19.6 hr, a DNA synthetic time of 8.3 hr, and a growth fraction of 1. Approximately 38% of cells are in S phase at one time. Hydroxyurea (HU) infusions (i.v.) at 1.17 mg/hr into tumor-bearing mice rapidly inhibit tumor DNA synthesis. Following a 5-hr HU infusion, 58% of all tumor cells are in S phase, and maximal tumor mitotic rates after release of the HU blockade are double control rates. HU was infused for 5 hr, followed by 7 hr of Ringer's solution, and then another 5 hr of HU. Following this 2-cycle blockade, 70% of tumor cells are in S phase, predominantly in early S phase and at the G1-S junction. After release, peak mitotic rates are 2.5 times control. The duration of the intermitotic time of the tumor following HU infusion is less than the total cell cycle time of control tumor. Cycles of HU infusion and release, timed according to the predetermined duration of the cell cycle intervals, will synchronize significant increments of S phase or mitotic cells of the Sarcoma 180 tumor during predictable periods of time.

Animals↗