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PubMed1991

Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma.

Inhibition of 5-lipoxygenase (5-LO) is a potential target for therapeutic intervention in asthma. Acetohydroxamic acids such as BW A4C are potent and selective 5-LO inhibitors in vitro and also inhibit 5-LO activity in vivo following oral administration. In man, BW A4C is metabolised relatively rapidly (t1/2 = approx. 2h) but nevertheless inhibits 5-LO with reasonable persistence. Chemical modification of BW A4C has resulted in compounds, including the alpha-methyl analogues BW B218C and BW A360C and the hydroxyurea BW B70C, that retain high in vitro potency as selective 5-LO inhibitors and, compared to BW A4C, have a higher potency and longer duration of action in vivo. Members of both the hydroxamic acid and hydroxyurea series of 5-LO inhibitors are presently being considered as potential anti-asthma drugs.

Anaphylaxis↗

PubMed1987

Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2'-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression.

Experiments were undertaken to explore whether in vitro exposure of a nonmetastatic murine tumor to chemotherapeutic drugs would affect the ability of this tumor to metastasize spontaneously. The tumor chosen was an aneuploid (near-tetraploid) spontaneously arising intraductal mammary adenocarcinoma (CBA-SP1), which normally fails to give rise to microscopic or macroscopic metastases after s.c. inoculation of cells. The drugs tested were 5-aza-2'-deoxycytidine (5-aza-dCyd) and hydroxyurea. We found that the injection of 1 X 10(5) uncloned drug-treated cells s.c. resulted in the emergence of gross and/or microscopically detectable metastases in the lungs of CBA mice. Individual clones derived from hydroxyurea-treated cells all produced metastases in a manner similar to the bulk culture injections. Clones of 5-aza-dCyd-treated cells also produced metastases, but fewer of these produced macroscopic metastases. In addition, only 9 of 15 5-aza-dCyd-treated clones produced tumor takes because of the ability of 5-Aza-dCyd to engender Imm+ variants in CBA-SP1 cells. Lung metastases obtained after the injection of uncloned cells retained their metastatic phenotype for three generations, indicating that the phenotypic change was a heritable characteristic. Although the genetic or epigenetic mechanism for this change is unknown, we observed karyotypic changes of a similar nature in the drug-treated cell lines established from micrometastases. These involved the detection of extra copies of chromosome 8. It is possible that exposure of tumors to therapeutic agents may in some cases increase their aggressiveness through genetic or epigenetic mechanisms that lead to high frequency heritable phenotypic alterations associated with distinguishable chromosomal changes.

Animals↗

PubMed1989

Establishment of donor hematopoiesis after hydroxyurea-induced aplasia following allograft failure in a patient with monosomy 7 variant of childhood chronic myelogenous leukemia.

Monosomy 7 variant childhood chronic myelogenous leukemia (CML) is a rare, fatal leukemia that usually terminates in blast crisis. We report successful marrow transplantation in a patient with this disease using his one HLA locus mismatched mother. Initially following transplant the patient exhibited mixed hematopoietic chimerism, cytogenetic relapse, and clinical relapse of leukemia. However, following recovery from a period of hydroxyurea-induced aplasia, marrow studies showed elimination of the mixed chimerism, absence of the 45,XY,-7 leukemic clone and full engraftment with donor marrow (46,XX). The ability of hydroxyurea to eliminate mixed chimerism in favor of donor hematopoiesis and to eliminate the persistent leukemic clone in this patient with CML suggests treatment approaches worthy of future investigation.

Bone Marrow↗

PubMed1989

Amplification of N-myc and ornithine decarboxylase genes in human neuroblastoma and hydroxyurea-resistant hamster cell lines.

The genes for the M2 subunit of ribonucleotide reductase (RRM2), ornithine decarboxylase (ODC1), and 55,000-Daltons protein (P5), are amplified in hydroxyurea-resistant hamster and human cell lines. These genomic sequences have been mapped to hamster chromosome 7 and to human chromosome 2p24-25 near the cytogenetic location of the N-myc gene. We now report that genomic sequences homologous to N-myc are amplified in hydroxyurea-resistant hamster lung cell line, 600H, and the N-myc gene segregates with hamster chromosome 7 in mouse-hamster somatic cell hybrids. The conserved linkage group consisting of the RRM2, ODC1, P5, and N-myc in the hamster and human genomes prompted our investigation of human neuroblastomas. We report here that genomic DNA from 1 of 6 primary neuroblastoma tumors containing amplified N-myc also contains amplified sequences homologous to a hamster ODC cDNA.

Adolescent↗

PubMed1989

Thymidine suicide and hydroxyurea kill ratios accurately reflect the proliferative status of stem cells (CFU-S).

We have previously found that on average 30% of hematopoietic stem cells (CFU-S) are in the S phase, which is at least three times the value published by others. Therefore, it seemed desirable to investigate the reliability of the methods used to measure the percentage of CFU-S in S phase. Various modifications of the [3H]thymidine suicide were tested and it could be demonstrated that results were not affected by them. Furthermore, results obtained with the [3H]thymidine suicide were compared to those obtained with methods utilizing hydroxyurea to kill CFU-S in S phase. The [3H]thymidine- and hydroxyurea-based methods gave parallel results. The parallel behavior validated all of these methods as reliable indicators of the turnover of CFU-S and presumably other stem cell populations.

Animals↗

PubMedDate not supplied

[Mutations of resistance to 6-thioguanine following roentgen irradiation and subsequent treatment with cytosine arabinoside combined with hydroxyurea in Chinese hamster cells in the G1 phase].

A study was made of the effect of two-hour treatment of Chinese hamster cells with cytosine arabinoside (AraC) combined with hydroxyurea (HU) at the G1 phase of the cell cycle on lethal and mutagenic effects of X-radiation (50 to 400 cGy). The inhibitors were shown to increase a spontaneous mutation level of the resistance to 6-thioguanine: this increase augmented by 3 times as the time the treatment increased from 1-2 to 6 h. However, while sharply enhancing the inactivating effect of X-radiation (the enhancement coefficient was 2.6) Arac+HU caused an additive, or a somewhat lesser, effect as estimated by the yield of mutations. It is suggested that AraC combined with hydroxyurea fail to modify the radiation-induced premutation damages.

Animals↗

PubMed1988

Inhibition of leukemic HL60 cell growth by transferrin-gallium: effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea.

Cellular requirements for iron during DNA synthesis are related to the increased activity of the iron-containing M2 subunit of ribonucleotide reductase, the enzyme responsible for the reduction of ribonucleotides to deoxyribonucleotides. We have previously shown that transferrin-gallium (Tf-Ga) inhibits cellular iron incorporation. In the present study, Tf-Ga-induced inhibition of HL60 cell growth and upregulation of Tf receptor density was reversed with hemin. Cells exposed to 2 mumol/L Tf-Ga for six hours or longer displayed a diminution in the electron spin resonance (ESR) spectroscopy signal of the tyrosyl radical of the M2 subunit of ribonucleotide reductase. The effect of Tf-Ga on the ESR signal was reversed by hemin. Tf-Ga decreased the incorporation of 14C-adenosine into DNA and decreased intracellular deoxyribonucleotide pools, with the maximum diminution seen in deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) pools. Exposure of cells to combinations of Tf-Ga and hydroxyurea (a known inhibitor of ribonucleotide reductase) resulted in a marked inhibition of cell growth that was consistent with drug synergy. Our studies suggest that Tf-Ga inhibits DNA synthesis through action on the M2 subunit of ribonucleotide reductase and that combinations of Ga and hydroxyurea should be further evaluated in in vivo tumor models.

Cell Division↗

PubMed1978

The influence of hydroxyurea and colchicine on growth and morphology of Trypanosoma cruzi.

Cultures of Trypanosoma cruzi have been exposed to the drugs hydroxyurea and colchicine. We found that hydroxyurea (200 microgram/ml) completely inhibited growth and differentiation of T. cruzi Y strain. Colchicine (200 microgram/ml) reduced the growth of T. cruzi 30% and stimulated cell differentiation from epimastigotes to trypomastigotes. Furthermore it caused anuclear cells with apparently intact kinetoplasts. The possible use of these anuclear forms in studies on kinetoplast DNA organization and expression is suggested.

Colchicine↗

PubMed1987

Hydroxyurea treatment of myeloproliferative disorders. Macro-megaloblastic blood and bone marrow changes.

Blood and bone marrow changes induced by continuous low-dose hydroxyurea treatment are described. A linear increase in mean red cell volume was observed after onset of therapy. The entire normocyte population was replaced by abnormally large erythrocytes within 150 days. The bone marrow morphology changed in megaloblastic direction. Bone marrow iron stores and number of sideroblasts increased, findings compatible with ineffective erythropoiesis. Serum folate and cobalamin levels remained normal. These morphologic changes might cause confusion when examining blood or bone marrow samples from patients treated with hydroxyurea.

Bone Marrow↗

PubMed1987

Utilization of hydroxyurea for detection of DNA repair synthesis in liver following dimethylnitrosamine action by means of scintillation counting.

We detected DNA repair synthesis by employing hydroxyurea as an inhibitor of DNA semiconservative synthesis in various time schedules of experiments. We came to the conclusion that prolongation of the time interval between [3H]thymidine administration and sacrifice of the animals from 0.5 h to 7.5 h increases the sensitivity of examination. Some artifacts associated with detection of the repair (hydroxyurea-resistant) synthesis of DNA are discussed.

Animals↗

PubMed1986

[Relation between the toxic killing of mouse small intestine enterocytes and the interval between the administration of the S-specific agent hydroxyurea].

The dependence of small intestinal lesions on the interval between repeated regular injections of hydroxyurea was studied. The doses of 1 g/kg and 0.2 g/kg were used. To activate the enterocyte proliferation the mice were pre-irradiated at 2 Gy. 3-4 hours after the last hydroxyurea injection the two distinct minimum points of epithelial lesions were observed at interinjection intervals of 9 and 16.5 hours. The result was dose-independent.

Animals↗

PubMedDate not supplied

[Megakaryocytopoiesis studied in a mathematical model. 2. Regulation of cell differentiation following damage to part of the proliferating bone marrow pool by hydroxyurea].

Analysis of the earlier obtained data on the effect of hydroxyurea on megakaryocytopoiesis by a simulation model has shown that differentiation of proliferating precursors of the megakaryocytes depends on their amount in bone marrow; the time of their involvement in the proliferating pool increases if the number of proliferating cells decreases. Within 24 h after the treatment with hydroxyurea (900 mg/kg), the transit time for the mouse megakaryocytes is reduced by about 14 h due to acceleration of the latest developmental stages. A hypothesis is put forward which accounts for correlation between the duration of proliferative period and the volume and maturation time of megakaryocytes.

Animals↗

PubMed1985

Giant cell formation in cultured L5178Y lymphoblasts induced by hydroxyurea treatment.

The conditions leading to hydroxyurea-induced abnormal cell enlargement (giant cell formation) were studied in L5178Y lymphoblasts in the culture. Exposure for only 1 hour to a concentration of 1 mM hydroxyurea (HU) was sufficient to produce an abnormal enlargement of about 25 percent of the cells. The maximal proportion of giant cells reached the value of about 50 percent after treatment with 1 mM HU for 5 hours and was not changed by a further prolongation of exposure time and/or by increasing the concentration of HU to 10 mM. Comparison of cell populations with various proportions of giant cells as regards their ability to reproduce, DNA synthesis and persistence in the culture suggested that at least some part of giant cells lost the ability to divide, their DNA synthesis was markedly suppressed or retarded and more than 50 percent of them disappeared earlier than 48 hours after the termination of HU exposure. It is concluded that at least at certain HU concentrations and in suitable stage of target cells the response of cells to short HU treatment can resemble that produced by X-rays or other DNA damaging agents.

Cells, Cultured↗

PubMed1985

Effects of hydroxyurea and thymidine derivatives on the uptake and metabolism of deoxycytidine and arabinofuranosylcytosine in log phase and contact-inhibited human diploid fibroblasts.

Hydroxyurea and pyrimidine analogs have been shown to enhance the chemotherapeutic efficacy and the DNA excision repair-inhibitory capacity of arabinofuranosylcytosine (ara-C). Since various cell types are expected to respond differently to these combination treatments and since little is known about the nature of their antiproliferative effects, we have investigated the metabolism and uptake into acid-soluble pools of deoxycytidine (dCyd) and ara-C in cycling and non-cycling human diploid fibroblasts. A substantial fraction of dCyd is converted through deamination to deoxyuridine and thymidine nucleotides, and this occurs to a greater degree in log phase cultures. ara-C is more resistant to deamination and is metabolized primarily to ara-CTP. Hydroxyurea decreases the proportion of dCyd and ara-C which is deaminated under both growth conditions, leading to higher levels of ara-CTP and dCTP. Trifluorothymidine causes an accumulation of dUMP and decreases the formation of dCTP in log phase and confluent cells. Thymidine inhibits deamination in log phase cells but stimulates this pathway in noncycling cells. Dideoxythymidine did not appreciably alter the spectrum of metabolites of dCyd formed in log or confluent phase cells but was shown to inhibit the transport of dCyd and thymidine across the membrane. These studies provide information regarding the nature of the enhancement of the antiproliferative activity of ara-C by commonly used drugs and indicate that the cycling state of the target cell plays a major role in determining the metabolism of the nucleoside and the efficacy of chemotherapeutic treatments.

Arabinofuranosylcytosine Triphosphate↗

PubMed1979

Differential cell-cycle-dependent inhibition of DNA synthesis by hydroxyurea and cytosine arabinoside in cultured L5178Y mouse lymphoma cells.

The effect of various concentrations of hydroxyurea and cytosine arabinoside on DNA synthesis, measured as 3H-thymidine incorporation, in exponentially growing and synchronized L5178Y cells in culture was investigated. The experiments revealed that each compound causes differential inhibition of DNA synthesis at various times of the S-phase. Maximum sensitivity to hydroxyurea occurred in cells in the late S, and maximum sensitivity to cytosine arabinoside in the early S-phase. When they were given simultaneously in low concentrations an additive effect was observed.

Animals↗

PubMed1977

Lethal and sublethal effects of hydroxyurea in relation to drug concentration and duration of drug exposure in sarcoma 180 in vitro.

The lethal and sublethal effects of hydroxyurea were studied in Sarcoma 180 in vitro in relation to drug concentration and drug exposure duration using cloning methods, radioautography, and flow microfluorometry. It was shown that postperturbation changes in radioautographic labeling intensity reflected real changes in the rate of DNA synthesis in individual cells. The data suggest that both the lethal and sublethal effects of hydroxyurea are dependent on the rate of DNA synthesis. These findings have important implications for the interpretation of DNA content distributions under perturbation conditions and for the development of drug treatment regimens that are based on cell kinetics.

Animals↗

PubMedDate not supplied

[Differential inhibition of synthesis and methylation of DNA fragments by hydroxyurea in L5178Y lymphoblasts in vitro].

In cultures of mouse L5178Y lymphoblasts treated with low concentrations of hydroxyurea during the logarithmic phase of growth differential inhibition of synthesis and methylation of various DNA fragments was observed. Some evidence is presented that the effect may be due to different sensitivity of cells to the action of hydroxyurea at various times of the S-phase.

Animals↗

PubMed1977

Description of a suicide technique in vitro for granulocytic stem cells (CFUc) by hydroxyurea on normal human bone marrow.

It has been possible, by studying 15 normal human bone marrow samples, to develop a technique for the suicide effect in vitro by hydroxyurea (H.U.), applied to human granulocytic stem cells (CFUc). This study suggests a contact time of medullary cells from 60 to 80 minutes in the presence of a hydroxyurea concentration 6 mM per 10(6) cells per ml in vitro. Preliminary results concerning the clusters are discussed.

Bone Marrow↗