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PubMed2006

Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine.

Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.

ADP-ribosyl Cyclase 1↗

PubMed1986

Potentiation of hydroxyurea cytotoxicity by iron-chelating agent in murine tumor models in vitro.

The biochemical modulation of tumor cell response to increase the cytotoxicity of Hydroxyurea (HU), directed at the ribonucleotide reductase enzyme, has been studied in in vitro. Mice bearing ascites tumor models such as L1210 leukemia, Sarcoma 180 (S180) and Ehrlich ascites tumor (EAT) were employed in this study. The cytotoxicity of HU alone at various concentrations was dose dependent and showed the following order of sensitivity; L1210 greater than EAT greater than S180. The hydrophobic iron-chelating agent 2,2-bipyridyl significantly potentiated the antitumor activity of HU in all the murine tumor models studied. In contrast, hydrophilic iron-chelator, Desferal, did not show any cytotoxicity when combined with HU. The present study demonstrated the factors influencing the amelioration of HU cytotoxicity and possible therapeutic use of iron-chelating agents alone and with HU for better therapeutic results in clinics.

2,2'-Dipyridyl↗

PubMed1986

Volumetric erythrocyte macrocytosis induced by hydroxyurea.

An atypical form of macrocytosis termed volumetric macrocytosis is described. In contrast to the macrocyte associated with megaloblastic anemia and the pseudomacrocyte caused by viscoelastic defects, the volumetric macrocyte is characterized by an increased mean corpuscular volume and a normal cell diameter. The volumetric macrocyte proves to be thicker than the normocytic red blood cell. This large erythrocyte is overhydrated and contains an increased quantity of hemoglobin. The cell has many characteristics in common with the red blood cells of neonates. Volumetric macrocytosis accompanies sustained hydroxyurea therapy and may represent a drug-induced dyserythropoiesis.

Blood Viscosity↗

PubMed1980

Hydroxyurea: protection of KB cells against the toxic effect of N-methyl-N'-nitro-N-nitrosoguanidine.

This report shows that hydroxyurea (HU) protected KB cells specifically against the toxic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). It appears unlikely that this action was due to stimulation of DNA repair since HU neither protected the cells when added after removal of MNNG, nor shielded them against the toxicity of other DNA damaging agents. Similarly, it seems difficult to account for HU protection by its specific effect as an inhibitor of DNA synthesis, because cell protection was found to be maximal when the proliferative activity of the cultures was minimal, and because much higher doses of HU were required to ensure cell protection than to inhibit DNA synthesis. In fact, the shift of the MNNG dose-response curves in the presence of increasing HU concentrations suggests that HU might interfere with the MNNG-molecule. This was confirmed by our finding that HU enhanced the decomposition rate of MNNG, as did other substances like cysteine or ascorbic acid, which also appeared able to protect the cells against the toxic effect of MNNG.

Ascorbic Acid↗

PubMed1982

Enhancement of methylnitrosourea skin carcinogenesis by inhibiting cell proliferation with hydroxyurea or skin extracts.

To study the relationship between epidermal DNA synthesis and carcinogenesis, groups of hairless mice were given a single skin application of 2 mg N-methyl-N-nitrosourea (MNU) in acetone. One group received no pretreatment, another group was injected i.p. with 5 mg hydroxyurea (HU) 30 min before MNU, and a further group with 0.5 mg Colcemid 3 h before MNU. Other groups were injected i.p. 14 and 4 h before MNU with either saline, 5 mg crude aqueous skin extract, 2 mg dialysed skin extracts of two types, or 2 mg dialysed extracts of liver or heart muscle, respectively. All substances were dissolved in 0.5 ml distilled water. Cell kinetic studies showed that the three skin extracts inhibited epidermal DNA synthesis and mitosis. HU inhibited DNA synthesis and increased the mitotic rate. The other pretreatments had no effect on epidermal DNA synthesis. There was a significant enhancement of the production of skin tumors in the groups pretreated with epidermal extracts or HU. MNU is a short-acting carcinogen with a half-life in the cell of 30 min. Hence, the results show that when DNA synthesis is inhibited at the time of MNU application, more tumors are produced in the skin. A possible explanation of the enhancement is that a compensatory wave of proliferation a short time after carcinogen binding may fix a DNA injury before repair can take place.

Animals↗

PubMed1982

Hydroxyurea enhances methylnitrosourea skin tumorigenesis when given shortly before, but not after, the carcinogen.

To study the relationship between epidermal DNA synthesis and carcinogenesis, hairless mice of both sexes were given a single topical application of 1 mg N-methyl-N-nitrosourea (MNU) in acetone. A control group received only MNU, whereas other groups were injected i.p. with 5 mg hydroxyurea (HU), 1 h, 45 min and 15 min before, simultaneously with, and 15 min, 30 min and 45 min after MNU application. The production of skin tumors was recorded and the results were assessed with accepted statistical methods. Injection of HU shortly before a single application of MNU enhanced skin carcinogenesis, and when HU is injected 30 min before MNU, the enhancement seems to be most pronounced. HU administered simultaneously with or following MNU application, did not alter the production of tumors. The cell kinetic situation in the epidermis at the time of a carcinogen application, and the modulation of the cell kinetic reaction to the carcinogen by any type of post- or pretreatment, may influence tumorigenesis.

Animals↗

PubMed1983

Cell growth state determines susceptibility of repair DNA synthesis to inhibition by hydroxyurea and 1-beta-D-arabinofuranosylcytosine.

The effects of inhibitors of replicative DNA synthesis on repair DNA synthesis have been examined by autoradiography in several different cell types and in cells in different growth states. Hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (ara C), administered together, influence unscheduled DNA synthesis (UDS) in a manner which is independent of the status of the cell culture (normal or transformed) and of the species, but which is strongly affected by whether the cells are proliferating or quiescent. In proliferating human, Chinese hamster and Microtus cell cultures, UDS is not inhibited by HU and ara C, and may even appear to be stimulated. In quiescent cultures of these cells UDS is reduced by HU and ara C. In cells reseeded from a confluent culture and followed during proliferation and back to quiescence the effect of inhibitors parallels the growth pattern. The results are interpreted in terms of changes in the sizes of endogenous DNA precursor pools; they underline the potential problems associated with quantitating UDS in the presence of inhibitors.

Animals↗

PubMed1988

Suppression of keratinocyte differentiation in SSC-9 human squamous carcinoma cells by benzo[a]pyrene, 12-O-tetradecanoylphorbol-13-acetate and hydroxyurea.

In the human squamous carcinoma cell line SCC-9, the expression of two markers of keratinocyte differentiation, involucrin and transglutaminase, was greatly stimulated when growing cultures reached confluence. However, the two markers differed temporally in their induction, with transglutaminase reaching maximal levels shortly after confluence and involucrin a week later. If replication was arrested with hydroxyurea prior to confluence, transglutaminase induction occurred within several days but involucrin levels were completely suppressed. Such a striking degree of uncoupling also resulted when the cells were treated with polycyclic aromatic hydrocarbons such as benzo[a]pyrene but not with 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent inducer of aryl hydrocarbon hydroxylase, or with pyrene. Chronic treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate suppressed expression of both transglutaminase and involucrin. However, suppression of the latter (evident in greatly reduced mRNA levels) was considerably more potent and powerful. These findings demonstrate uncoupling of keratinocyte differentiation, potentially useful in analysis of its multiple regulatory influences. They also emphasize the utility of sensitive keratinocyte targets for studying the mechanisms by which model carcinogens disturb the orderly progression of events in their differentiation program.

Benzo(a)pyrene↗

PubMed1998

Isolation of a Schizosaccharomyces pombe rad21ts mutant that is aberrant in chromosome segregation, microtubule function, DNA repair and sensitive to hydroxyurea: possible involvement of Rad21 in ubiquitin-mediated proteolysis.

The fission yeast DNA repair gene rad21+ is essential for cell growth. To investigate the function essential for cell proliferation, we have isolated a temperature-sensitive mutant of the rad21+ gene. The mutant, rad21-K1, showed abnormal mitosis at the nonpermissive temperature. Some cells contained abnormal nuclear structures, such as condensed chromosomes with short spindles, or chromosomes stretched or unequally separated by elongating spindles. Other cells exhibited the displaced nucleus or a cut-like phenotype. Similar abnormalities were observed when the Rad21 protein was depleted from cells. We therefore concluded that Rad21 is essential for proper segregation of chromosomes. Moreover, the rad21-K1 mutant is sensitive not only to UV and gamma-ray irradiation but to thiabendazole and hydroxyurea, indicating that Rad21 plays important roles in microtubule function, DNA repair, and S phase function. The relation to the microtubule function was further confirmed by the fact that rad21+ genetically interacts with tubulin genes, nda2+ and nda3+. Finally, the growth of the rad21-K1 mutant was inhibited at the permissive temperature by introduction of another mutation in the cut9+ gene, coding for a component of the 20S cyclosome/anaphase promoting complex, which is involved in ubiquitin-mediated proteolysis. The results suggest that these diverse functions of Rad21 may be facilitated through ubiquitin-mediated proteolysis.

Cell Cycle Proteins↗

PubMed2000

A case of bilateral heel ulcers associated with hydroxyurea therapy for chronic myelogenous leukemia.

Bilateral heel skin ulcers developed in a 50-year-old male in the chronic phase of chronic myelogenous leukemia who had been receiving hydroxyurea (HU) therapy for 3 years. Histological examination showed perivascular lymphocytic inflammation without vasculitis. After interruption of HU administration, the heel ulcers were completely resolved within 2 months. The clinical course strongly suggested that the heel ulcers were induced by long-term HU therapy.

Antineoplastic Agents↗

PubMed2000

Essential thrombocythemia transformed to acute myelogenous leukemia with t(3;17)(p24; q12), del(5)(q13q34) after treatment with carboquone and hydroxyurea.

In 1991, a 52-year-old woman was diagnosed as having essential thrombocythemia (ET). She was doing well with continuous medication with carboquone (CQ) and subsequently hydroxyurea (HU). However, substantial leukocytosis with leukemic blast cells, anemia and thrombocytopenia developed in 1996. Analysis of peripheral blood showed 4.4 x 10(3)/microl white blood cells with 82% of leukemic blast cells. These blasts showed negative staining with myeloperoxidase by immunostaining, but the myeloperoxidase was positive by electron microscopic analysis. Cytogenetic analysis of bone marrow cells revealed a t(3;17)(p24; q12), del(5)(q13q34). On the basis of these findings, the leukemic blast cells were classified as acute myelogenous leukemia (AML:M0) in the FAB classification. The causative agent, CQ and HU in secondary leukemia from ET and chromosomal abnormality related to ET blastic crisis (BC) are discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1979

Hematopoietic stem cells in Friend murine leukemia virus-infected mice undergoing chemotherapy: remission and relapse of erythropoietin-independent erythropoiesis induced by hydroxyurea.

Hydroxyurea (HU), given ip four times, each time at 500 mg/kg in 6-hour intervals, was used to treat DBA/2 mice with Friend murine leukemia virus-induced polycythemia (F-MuLV-P). In these mice a new cell type, found after virus infection, gave rise to erythropoietic colonies in vitro without addition of erythropoietin (Ep) and completely replaced Ep-dependent normal erythropoietic colonies in vitro. The colony-forming units in the spleen (CFUs), the colony-forming units in culture (CFUc), and the erythropoietic colony-forming units (CFUE) were studied. Two days after treatment, CFUs were reduced to about 20% in controls and F-MuLV-P-infected animals, and CFUc were reduced to 6-11% in controls and F-MuLV-P-infected animals. CFUE were not detectable. At day 4 after the first HU dose, when CFUs has regenerated to about normal levels, a sharp rise in Ep-dependent CFUE was seen in the marrow; this rise was not present before HU treatment. The subsequent fall at day 7 coincided with a regeneration of CFUE in the spleen, but in the spleen these CFUE were all Ep-independent. Possibly, the normal Ep-dependent CFUE during regeneration in the marrow might have derived from previously resting CFUs that were not killed by HU. The subsequent conversion to Ep independency could have been due to reinfection by F-MuLV-P persisting in the animal.

Animals↗

PubMed1986

Potentiation by 1-alpha,25-dihydroxyvitamin D3 of cytotoxicity to HL-60 cells produced by cytarabine and hydroxyurea.

A short (4-hr) exposure to 1-4 X 10(-7) M 1,25-dihydroxyvitamin D3 [(1,25(OH)2D3); 1-alpha,25-dihydroxycholecalciferol] induced transient differentiation in a clone (R2AB2) of human promyelocytic leukemia cells (HL-60) but caused no permanent growth impairment and no detectable cytotoxicity. This treatment with 1,25(OH)2D3 also produced an inhibition of DNA synthesis that was promptly reversed when 1,25(OH)2D3 was removed. When such treatment with 1,25(OH)2D3 immediately followed a sublethal exposure to drugs that inhibit DNA synthesis, including the cancer chemotherapeutic agents cytarabine and hydroxyurea, the proportion of HL-60 cells lethally damaged was increased. This finding was demonstrated by morphologic evidence of cell damage and disintegration, an increased permeability to trypan blue, loss of cells from culture, and a reduced clonogenic potential of the treated cells. Exposure to 1,25(OH)2D3 before treatment with a cytotoxic agent had a slightly protective rather than a damaging effect. These observations suggest that the presence of 1,25(OH)2D3 markedly reduces the capacity of HL-60 cells to repair DNA damage or to reduce the intracellular concentration of cytotoxic agents.

Calcitriol↗

PubMed1994

The origin of micronuclei induced by cytosine arabinoside and its synergistic interaction with hydroxyurea in human lymphocytes.

Using human lymphocytes and the cytokinesis-block micronucleus (CBMN) assay we have recently shown that excision-repairable DNA lesions induced by methylnitrosourea (MNU) and ultraviolet (UV) light (254 nm) can be converted to micronuclei (MNi) within one cell cycle if cytosine arabinoside (ARA-C) is added during the G1 phase of the cell cycle after mitogen stimulation. We have proposed that this conversion resulted from the inhibition by ARA-C of the gap-filling step during excision repair which results in the formation of single-stranded breaks at repair sites; these breaks are then converted to chromatid or chromosome breaks and subsequently to MNi on completion of nuclear division. To confirm this hypothesis we have examined the origin of MNi induced by ARA-C by using anti-kinetochore antibodies and found that between 77 and 86% of these MNi are kinetochore-negative which supports the idea that they originate mainly from acentric chromosome fragments. We have also demonstrated that combining ARA-C treatment with hydroxyurea (HU) during G1 provides a synergistic improvement in the conversion of spontaneous (4-fold increment) or MNU-induced (2-fold increment) excision-repairable DNA lesions to MNi when compared to the effects with ARA-C alone. HU treatment on its own did not influence micronucleus expression in untreated cells and cells treated with MNU.

Adult↗

PubMed2000

Mutant alleles of Schizosaccharomyces pombe rad9(+) alter hydroxyurea resistance, radioresistance and checkpoint control.

Schizosaccharomyces pombe rad9 mutations can render cells sensitive to hydroxyurea (HU), gamma-rays and UV light and eliminate associated checkpoint controls. In vitro mutagenesis was performed on S.pombe rad9 and altered alleles were transplaced into the genome to ascertain the functional significance of five groups of evolutionarily conserved amino acids. Most targeted regions were changed to alanines, whereas rad9-S3 encodes a protein devoid of 22 amino acids normally present in yeast but absent from mammalian Rad9 proteins. We examined whether these rad9 alleles confer radiation and HU sensitivity and whether the sensitivities correlate with checkpoint control deficiencies. One rad9 mutant allele was fully active, whereas four others demonstrated partial loss of function. rad9-S1, which contains alterations in a BH3-like domain, conferred HU resistance but increased sensitivity to gamma-rays and UV light, without affecting checkpoint controls. rad9-S2 reduced gamma-ray sensitivity marginally, without altering other phenotypes. Two alleles, rad9-S4 and rad9-S5, reduced HU sensitivity, radiosensitivity and caused aberrant checkpoint function. HU-induced checkpoint control could not be uncoupled from drug resistance. These results establish unique as well as overlapping functional domains within Rad9p and provide evidence that requirements of the protein for promoting resistance to radiation and HU are not identical.

Alleles↗

PubMed1993

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.

BACKGROUND: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). PATIENTS AND METHODS: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. RESULTS: Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml. CONCLUSIONS: The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.

Adult↗

PubMed1986

Hydroxyurea and 6-mercaptopurine in the treatment of chronic granulocytic leukemia.

From 1975 to 1981, 92 patients with newly diagnosed Ph'-positive chronic granulocytic leukemia entered two consecutive studies. The initial trial (Study I, 1975-1978) tested the efficacy of hydroxyurea (HU) as single agent in 45 consecutive patients. In an effort to improve results obtained with HU alone, from 1978 to 1981, 47 new patients entered a second trial (Study II), which consisted of a continuous treatment with a combination of HU and 6-mercaptopurine (6-MP), at doses adjusted so as to maintain the leukocyte counts between 4 and 12 X 10(9)/L. The aim of this second study was to prolong the duration of chronic phase (CP) by the addition of 6-MP to HU and by a stricter continuous control of the size of the total granulocytic mass (TGM). Both regimens were well tolerated. Median duration of CP was 43 months in Study I and 41 months in Study II. Median survival was 51.5 months and 45 months respectively. These data indicate that neither the addition of 6-MP to HU alone, nor the effort to keep a smaller TGM, play a substantial role in postponement of blastic transformation in CGL.

Adult↗

PubMed1987

cis-platinum, 5-fluorouracil, and hydroxyurea in the treatment of advanced non-small-cell lung cancer. A phase II study.

Sixteen patients with advanced non-small-cell lung cancer were treated with the combination of cis-platinum, 5-fluorouracil, and hydroxyurea. There were two complete responses (lasting 16 weeks each) and one partial response (lasting 12 weeks). Toxicity was manageable, but responders were unable to tolerate further therapy. Despite the obtaining of complete responses, the overall benefit of this particular combination requires further clinical investigation.

Adenocarcinoma↗