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PubMed2003

Hydroxyurea (HU)-induced apoptosis in the mouse fetal tissues.

Hydroxyurea (HU), a ribonucleotide reductase inhibitor, induces morphological anomalies in the central nervous system (CNS), craniofacial tissues and limb buds in animals, and neonatal respiratory distress in humans. In the present study, pregnant mice were treated with 400 mg/kg of HU at day 13 of gestation, and their fetuses were examined from 1 to 48 hours after treatment (HAT) to find a clue to clarify the mechanisms of HU-induced fetotoxicity and teratogenecity. At 6 and 12 HAT, a moderate to marked increase in the number of pyknotic cells was detected in the CNS and lung. A mild increase in the number of pyknotic cells was also found in the craniofacial mesenchymal tissues, limb buds and so on. These pyknotic cells had nuclei positively stained by the TUNEL method, which is widely used for the detection of apoptotic nuclei, and they also showed electron microscopic characteristics identical to those of apoptotic cells. The present results suggest that the HU-induced fetotoxicity is characterized by excess apoptotic cell death in the fetal tissues, and that such excess cell death in the fetal CNS, lung, craniofacial tissue and limb bud may have a certain relation to the later occurrence of morphological or functional anomalies reported in these tissues following HU-administration.

Animals↗

PubMed2005

Anagrelide does not exert a myelodysplastic effect on megakaryopoiesis: a comparative immunohistochemical and morphometric study with hydroxyurea.

A comparative immunohistochemical and morphometric study was performed on megakaryocytes in 20 patients presenting with initial-early stage chronic idiopathic myelofibrosis and accompanying thrombocythemia to elucidate histological features developing after hydroxyurea (HU) versus anagrelide (ANA) therapy. Representative pre-and posttreatment bone marrow biopsies were involved including the monoclonal antibody CD61 for the identification of precursor and mature stages of megakaryopoiesis. An elaborate morphometric evaluation was in keeping with a left-shifting showing a more frequent occurrence of promegakaryoblasts and microforms in both therapy groups. However, contrasting ANA, HU generated defects of differentiation consistent with significant dysplastic changes. In conclusion, concern about a possible leukemogenic capacity following long-term HU therapy is supported by our findings.

Antineoplastic Agents↗

PubMed1987

In utero morphological effects of hydroxyurea on the fetal development in Sprague-Dawley rats.

In order to investigate in utero morphological effect of hydroxyurea (HU) in Sprague-Dawley rats, HU was intraperitoneally injected to pregnant Sprague-Dawley rats at a dose of 100 or 200 mg/kg/day during the organogenetic period (days 9-12 of gestation). A dose of 200 mg/kg/day induced growth retardation, high mortality and high incidence of malformations, although a dose of 100 mg/kg/day produced no adverse effects in the next generation. In the HU 200 mg/kg/day group the incidence of malformations in pups at 4 days of age was low as compared with that in fetuses and pups at 21 days of age. Increasing perinatal mortality in fetuses and pups due to severe central nervous system (CNS) malformations and disappearance of some cases of ventricular septal defect after delivery were considered as the possible causes to induce difference in malformation rate in various stage of development. Latent effect on the development of CNS malformations was observed between 4 and 21 days of age. There was no sex difference in teratogenic effect. These findings were compared with those in Wistar rats exposed to HU 200 mg/kg/day. The incidence of perinatal malformations and the stillbirths were significantly higher in the Wistar rats as compared with those in the Sprague-Dawley rats. In addition, such morphological effects of HU as the exencephaly, dilatation of lateral ventricle, anophthalmia, cleft palate and micrognathia are less severe in Sprague-Dawley rat fetuses than in Wistar rat fetuses.

Abnormalities, Drug-Induced↗

PubMed1999

New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and thalidomide.

The tenacious effort to develop new, specific agents to treat HIV infection is currently accompanied by a reconsideration of existing drugs on the basis of their known or putative effects on the retroviral life cycle and/or the tuning of immune mechanisms. Three specific 'older' compounds that interfere with HIV infection by both a direct antiviral activity, and a modulation of T-cell activation and proliferation have received the most attention. Hydroxurea, a classical chemotherapeutic agent, inhibits retroviral reverse transcription by targeting a cellular enzyme responsible for the synthesis of deoxynucleoside triphosphates. It may also have a role in reducing viral load while maintaining low numbers of potential target T cells. Beneficial effects of hydroxyurea in combination with didanosine and/or stavudine on viral load have been shown in a number of clinical trials. Cyclosporin, a known immunosuppressant, blocks the activation of T cells, hence reducing the permissivity to HIV, and also prevents proper HIV virion maturation. However, clinical studies have produced conflicting results in HIV-infected patients with regard to immunological and disease effects and toxicity. Thalidomide may have antiretroviral effects as a result of its primarily inhibitory effects on the production of tumour necrosis factor alpha (TNFalpha). TNFalpha induces expression of HIV from chronically infected cell lines by stimulating a cellular transcription factor, and blocking of TNFalpha-stimulated HIV replication by thalidomide has been shown in vitro and ex vivo. However, the effects on TNFalpha production in vivo have been inconsistent. Thalidomide has shown potential in treating some AIDS-related conditions [cachexia (weight loss and muscle wasting), and aphtous oral, oesophageal or genital ulcers]. However, because of its numerous and major adverse effects, thalidomide should always be used cautiously. In summary, some older drugs have potential as anti-HIV agents and offer the advantage of extensive clinical experience in other therapeutic areas. They should be considered as potential partners for the products emerging from more recent research and development.

Cyclosporine↗

PubMed1979

Radiation sensitivity change of hemopoietic cells induced by hydroxyurea.

Hemopoietic tissues of mice contain cells capable of proliferation and differentiation to form endogenous spleen colonies (Endo-CFU-S) in irradiated animals. Hydroxyurea (HU) given before irradiation of C57BL mice for endogenous CFU assay increased the number of surviving CFU-S twofold. Either HU or HSATT given after the initial stimulus abolished this rise. In vivo and in vitro 'suicide' assays of spleen cells indicated that cells were stimulated by the HU or the initial stimulus to enter into DNA synthesis shortly after stimulation. The resting CFU cell population appeared to be positioned close to DNA-S phase and responded to the stimulus by entry into S phase. Whole body irradiation at intervals after HU revealed a changing radiation sensitivity of the endogenous CFU-S consistent with drug-induced progression with decreased radiation sensitivity of the S phase cohort of cells.

Animals↗

PubMed1996

Hydroxyurea may increase the activity of fluorouracil plus folinic acid in advanced gastrointestinal cancer: phase II study.

In a phase II trial, 36 patients with advanced gastrointestinal cancer were treated with: folinic acid (FA) 500 mg/m2 in a 2-hr intravenous (IV) infusion, 5- fluorouracil (5-FU) 600 mg/m2 as an IV push injection 1 hr after FA, and hydroxyurea (HU) 35 mg/kg/day given p.o. in three administrations (every 8 hr) 6 hr after 5-FU. Cycles consisted of six weekly treatments for 6 weeks, followed by a 2-week rest period. Thirty-three patients were evaluable for response and 36 for toxicity; 73% had previous chemotherapy. The response rate was 30% (CR + PR), the median duration of response was 21 weeks (range 5-36), and time to failure was 17 weeks (range 3-51). The response in patients previously exposed to chemotherapy was 29% and 44% in chemotherapy-naïve patients. The median survival for all entered patients was 28 weeks (range 6-54). The most common toxicity was gastrointestinal: diarrhea 22/36 (61%), mucositis 15/36 (42%), and nausea and vomiting 15/36 (42%); hematological toxicity was mild. We conclude that HU can potentiate the activity of 5-FU plus FA in advanced gastrointestinal cancer; in particular, HU can restore the activity of 5-FU in patients previously exposed to chemotherapy.

Adult↗

PubMed1995

MIP-1 alpha increases the self-renewal capacity of the hemopoietic spleen-colony-forming cells following hydroxyurea treatment in vivo.

In this report, the effect of macrophage inflammatory protein (MIP-1alpha) on the self-renewal, in vivo, of haemopoietic spleen colony-forming units (CFU-S) following cytotoxic damage, has been investigated. CFU-S recovery following injection of hydroxyurea, HU (1 g/kg at 0 and 7 hers) with or without MIP-1alpha intervention was measured over the following 5 days. In addition to the initial protection conferred by MIP-1alpha, the CFU-S population recovered about 1.7 times faster than in the unprotected controls. Direct measurement of the self-renewal capacity of the CFU-S population was made at 2 days after HU + MIP-1alpha treatment by measuring the number of CFU-S/spleen colony in a secondary transplant assay. CFU-S following HU treatment alone generated 60 CFU-S/colony. Additional MIP-1alpha treatment increased this to 90 CFU-S/colony. It is concluded that MIP-1alpha modifies the generation age structure of a regenerating CFU-S population such that recovery is initiated from the more primitive cells of the population's age spectrum and that this observation should extend the range of cytotoxic agents from which MIP-1alpha can give protection.

Animals↗

PubMed2001

Molecular remission following high-dose hydroxyurea and fludarabine plus cytarabine in a patient with simultaneous acute myeloid leukemia and low-grade lymphoma.

The occurrence of acute myeloid leukemia (AML) as a secondary tumor has been frequently reported in patients who received various chemotherapy regimens for hematologic malignancies wile the concomitant development of chronic lymphoproliferative diseases (CLD) and AML in previously untreated patients is extremely rare. We report a case with an apparently spontaneous occurrence of AML and non Hodgkin low-grade lymphoma diagnosed by immunological, cytogenetical and molecular analyses. In particular genetic studies allowed to identify the coexistence of a clonal lymphoid population and a myeloid blast component characterized by inv(16) marker and CBFbeta-MYH11 gene fusion. Complete remission of AML and the CLD was obtained following high doses of hydroxyurea and two consolidation cycles of fludarabine plus intermediate dose cytarabine.

Acute Disease↗

PubMedDate not supplied

Comparative effects of interferon and hydroxyurea on bone marrow fibrosis in chronic myelogenous leukemia.

Therapy-related changes of the bone marrow fiber content remain a controversial issue in hematopathology. This conflict of opinion firstly depends on difficulties to determine the quantity of fibers exactly (semiquantitative grading, morphometry, reference to cellularity). Secondly, the appropriate selection of patients with specific monotherapies including hydroxyurea (HU) and interferon-alpha (IFN) seems to present some problems. Finally, assessment of myelofibrosis is further biased by the different endpoints of sequential examinations. The latter shortcoming can be improved upon by the calculation of the myelofibrosis progression/regression index which describes the ratio between difference of fiber density and observation time. Using strictly defined therapeutic regimens and intervals between sequential trephine biopsies a stimulating effect of IFN administration on bone marrow fibrosis in Ph1+-chronic myelogenous leukemia (CML) has been found. This result is comparable with the failure of this agent to improve myelofibrosis (and splenomegaly) in a considerable number of patients with allied subtypes of chronic myeloproliferative disorders. This is in contrast to the effect HU exerts which is a more fibrolytic or even stabilizing influence on bone marrow fibrosis. This phenomenon is readily demonstrable by the assessment of dynamic features (myelofibrosis progression index). In addition, patients showing a rapid progression of myelofibrosis during IFN and HU treatment of Ph1+-CML are generally associated with a poor risk outcome and a significant worsening of survival.

Humans↗

PubMedDate not supplied

Hydroxyurea-associated platelet count oscillations in polycythemia vera: a report of four new cases and a review.

Cyclic oscillations in the peripheral blood platelet count were recently described in two patients with polycythemia vera (PV) receiving therapy with hydroxyurea (HU). This phenomenon can make proper HU dosing very challenging and may be especially problematic in PV patients who are at risk for thrombohemorrhagic complications. In this report, we describe four new cases of HU-associated platelet oscillations in patients with PV and extend our observations on one of the two previously reported cases. We also review cyclic thrombocytosis within the broader context of periodic hematopoiesis. A thrombopoietin-mediated negative feedback loop is central to most models of periodic thrombopoiesis, but this is probably an oversimplification. It is possible that HU destabilizes the delicate balance of thrombopoietin/c-Mpl signaling in megakaryocytic lineage hematopoiesis that is already markedly altered in PV; this hypothesis remains speculative. For patients who develop oscillatory variation in their platelet counts associated with HU use, keeping the HU dose constant may result in damping or termination of the cycles. However, this strategy is not always successful.

Adult↗

PubMed1993

High dose hydroxyurea in collection of Philadelphia chromosome-negative stem cells in chronic myeloid leukaemia.

High dose hydroxyurea (HU) was used in a pilot study to assess its efficacy in mobilizing Philadelphia (Ph) chromosome negative progenitor cells in chronic myeloid leukaemia (CML). Five patients received 12 g/M2 oral HU in divided doses. Side effects were minimal, allowing outpatient administration. Nine to fourteen days later 4 patients achieved a mean leukocyte nadir of 3.5 x 10(9)/L (Range 2.4-4.9) and a mean platelet nadir of 99 x 10(9)/L (Range 95-108). Peripheral blood mononuclear cells (PB-MNC) sampled prior to the HU priming were 100% Ph positive. Between 10 and 18 days post HU, 3 patients achieved a marked reduction (80-100%) in the number of Ph positive metaphases in PB-MNC collected by apheresis. One patient failed to achieve any Ph suppression. Polymerase chain reaction analysis (PCR) for the bcr-abl fusion product remained positive in all samples. Rapid rises in CFU-GM numbers were associated with a return to 100% Ph positive metaphases however slower rises represented recovery with predominantly Ph negative cells, allowing apheresis collection of these cells. We conclude that HU induces a reproducible leukocyte nadir with sufficient stem cell mobilization for potential autologous transplantation. Higher doses of HU together with early and intensive apheresis is required to maximize Ph negative progenitor cell harvests.

Aged↗

PubMed1995

Successful treatment of accelerated and blastic phase of chronic myeloid leukemia with high-dose interferon alpha and hydroxyurea: a novel approach.

Six patients with either acceleration or blast crisis of transformed chronic myeloid leukemia (CML) were treated with high-dose interferon alpha in combination with hydroxyurea. All patients responded to the treatment by reversal to stable chronic phase. Two of these patients responded repeatedly during their course of disease. Median time for return to chronic phase was 4 weeks. Adverse side-effects such as nausea, vomiting, hairloss, fever, prolonged cytopenia were not observed.

Acetaminophen↗

PubMed1985

Phase III comparison of BCNU and the combination of procarbazine, CCNU, and vincristine administered after radiotherapy with hydroxyurea for malignant gliomas.

The authors report the results of a randomized study conducted to evaluate the relative benefit of treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine (PCV) administered after radiation therapy with hydroxyurea to 76 evaluable patients with glioblastoma multiforme and 72 patients with other anaplastic gliomas. The primary end-point of the study was time to tumor progression. For better-risk patients with Karnofsky performance scores of 70 to 100, results suggest that PCV was of greater benefit than BCNU (p = 0.15 for glioblastoma multiforme; p = 0.13 for other anaplastic gliomas). Median times to tumor progression were 31 and 32 weeks for patients with glioblastoma multiforme; 25th percentile times to progression were 70 and 40 weeks for patients treated with PCV and BCNU, respectively. For patients with other anaplastic gliomas treated with PCV and BCNU, median times to progression were 123 and 77 weeks, respectively. Multivariate analysis showed that the prognostic variables of age and Karnofsky scores were important for patients with glioblastoma multiforme and other anaplastic gliomas, and that the extent of surgical resection was important for those with other anaplastic gliomas.

Adult↗

PubMed1975

Hydroxyurea-induced erythroid differentiation.

Hydroxyurea, a cytotoxic agent which destroys cells in DNA synthesis, has been shown to evoke the differentiation of a small number of hemopoietic precursor cells in the erythroid series of erythropoietically suppressed hypertransfused mice. This effect does not appear to be mediated by erythropoietin (EP) since the simultaneous injection of anti-EP did not alter this response.

Animals↗

PubMed2004

Hydroxyurea-induced apoptosis in an EBV-immortalized lymphoblastoid cell line.

Hydroxyurea (HU) is an inhibitor of nucleotide synthesis extensively used to control the chronic phase of myeloid leukemia. This antimetabolite has been employed in the clinic for several decades but in recent years the leukemogenic potential of HU has been suspected. In the present study, a B-lymphoblastoid cell line transformed by the Epstein-Barr virus was used to investigate the apoptotic effects of HU and delineate some of the molecular pathways implicated in the cytotoxic action. The cell line, characterized by immunophenotyping, cytogenetic and fluorescence in situ hybridization (FISH) studies, showed no chromosomal abnormalities, even after a prolonged exposure to HU. Different flow cytometry assays were used to measure HU-induced impairment of the cell cycle, inhibition of DNA synthesis, and the occurrence of apoptosis. The treatment with HU leads to the appearance of a hypo-diploid DNA content peak (sub-G1) characteristic of the apoptotic cell population. The drug also induces a cell block in S phase as measured by 5-bromo-2'-deoxyuridine (BrdU) incorporation. Inhibition of DNA synthesis precedes induction of apoptosis by HU. A drug-induced loss of plasma membrane asymmetry was characterized by flow cytometry using annexin V-FITC to stain phosphatidylserine residues. The implication of the antiapoptotic protein Bcl-2 and the tumor suppressor p53 in the development of HU-mediated apoptosis was also evidenced. The drug appears to promote cell death by regulating the expression levels of these two proteins. Different criteria define the apoptotic response of the lymphoblastoid cells to the treatment with HU. However, the extent of drug-induced cell death is limited, and no DNA fragmentation and no activation of the caspase cascade was observed in this model. Beyond the specific interest in HU-induced apoptosis, the work reported here illustrates the utility of the EBV immortalization process to investigate the pharmacological activity of specific drugs from clinical samples.

Apoptosis↗

PubMed2005

ATR activation necessary but not sufficient for p53 induction and apoptosis in hydroxyurea-hypersensitive myeloid leukemia cells.

Hydroxyurea (HU) is a competitive inhibitor of ribonucleotide reductase that is used for the treatment of myeloproliferative disorders. HU inhibits DNA replication and induces apoptosis in a cell type-dependent manner, yet the relevant pathways that mediate apoptosis in response to this agent are not well characterized. In this study, we employed the human myeloid leukemia 1 (ML-1) cell line as a model to investigate the mechanisms of HU-induced apoptosis. Exposure of ML-1 cells to HU caused rapid cell death that was accompanied by hallmark features of apoptosis, including membrane blebbing, phosphatidylserine translocation, and caspase activation. HU-induced apoptosis required new protein synthesis, was induced by HU exposures as short as 15 min, and correlated with the accumulation of p53 and induction of the p53 target gene PUMA. p53 induction in ML-1 cells was ATR dependent and downregulation of p53 through RNAi delayed HU-induced apoptosis. HU did not induce p53 or induce apoptosis in Molt-3 leukemia cells, even though exposure to HU induced a comparable level of DNA damage and robustly activated the ATR pathway. The microtubule inhibitor nocodazole suppressed HU-induced p53 accumulation in ML-1 cells suggesting that a microtubule-dependent event contributes to p53 induction and apoptosis in this cell line. Our findings outline an HU-induced cell death pathway and suggest that activation of ATR is necessary, but not sufficient, for stabilization of p53 in response to DNA replication stress.

Apoptosis↗

PubMed1999

Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea.

In this project we have prospectively studied the erythropoietic activity in patients with sickle cell anaemia (SS) before and after treatment with hydroxyurea (HU). Some of the patients were enrolled in a double-blind placebo controlled trial of HU in patients with SS and others were enrolled in an open label study. Determinants of erythropoietic activity included the reticulocyte count, red blood cell (RBC) survival by the 51Cr method, plasma 59Fe clearance, plasma iron turnover (PIT), erythron transferrin uptake (ETU), RBC production/destruction rate, and RBC Fe utilization. Therapy with HU increased the mean corpuscular volume (MCV), haemoglobin (Hb)F, RBC survival and t1/2 59Fe clearance; it decreased the reticulocyte count, the white blood cell (WBC) count, ETU, and the PIT. Most of the changes in parameters of erythropoiesis could be explained by the increase in 51Cr RBC survival after therapy with HU. Together the data showed that in selected patients the net effect of HU on Hb level was a function of the difference between the suppressive effect of HU (decreased RBC production) and the increase in RBC survival. In the majority of patients who responded to HU, there was a preferential effect on RBC survival.

Adult↗

PubMedDate not supplied

5-Fluorouracil plus high dose levofolinic acid and oral hydroxyurea for the treatment of primary hepatocellular carcinomas: results of a phase II multicenter study of the Southern Italy Oncology Group (G.O.I.M.).

A phase II trial of 5FU in modulation with intravenous high-dose levofolinic acid and oral hydroxyurea (HU) in advanced unresectable hepatocellular carcinoma (HCC). A total of 50 consecutive patients, 38 males (76%) and 12 females (24%), with a mean age of 62 years (range 30-74) and a mean performance status of 80 (KI, range 60-90) were enrolled. The vast majority of patients were therapy-naive, although two patients (4%) had previous surgery and showed progressive disease at entry. No patient had been previously treated with chemotherapy. Five patients had previous hormonotherapy with tamoxifen. Most patients had disease limited to the liver while 12 patients (24%) had also metastatic deposits outside the liver. The treatment plan included: levofolinic acid 100 mg/m2 diluted in 500 cc of normal saline over 2 hour infusion followed by 5FU 600 mg/m2 i.v. bolus. HU 1,000 mg/m2 was given by mouth in three refracted doses starting 6 hours after 5FU. A PR was recorded in only 5 patients (10%; 95% CL 1%-34%) with a median duration of 5.7+ months (range 4.0/6.2 months), a stabilization in 15 (30%) with a median duration of 3.8 months, while 30 patients progressed (60%). PR were seen at liver primary tumor in 4 cases and at soft tissue in 1 case. The median survival was 5.8 months (range 2.0/12.0+). The most frequent toxicities were leukopenia (32%), which however was mild (grade 1-2) in all cases, and grade 1-2 thrombocytopenia observed in 15% of cases. Mild grade 1-2 vomiting was recorded in one third of patients, and grade 1-2 stomatitis in 15%. The combination of 5FU with levofolinic acid and oral HU on a weekly schedule is largely inactive against unresectable or metastatic HCC and results are no better than historical data reported for 5FU alone.

Adult↗