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PubMed1977

Differential cytotoxicity between transformed and normal human cells with combinations of aminonucleoside and hydroxyurea.

Normal human WI-38 cells can be protected from killing by hydroxyurea if proliferation is arrested during drug treatment. This protection was demonstrated both in cells arrested by density-dependent inhibition and by 3'-amino-3'deoxy-N6,N6-dimethyladenosine (puromycin aminonucleoside). In contrast, VA-13 cells (a simian virus 40-transformed clone of WI-38) were not arrested under these conditions, and continued to be sensitive to hydroxyurea. These results suggest that a search for agents that selectively and reversibly inhibit normal cycling human cells might lead to an enhancement of differential tumor toxicity.

Cell Division↗

PubMed1997

Hydroxyurea induces the gene expression and synthesis of proinflammatory cytokines in vivo.

The anticancer agent hydroxyurea (HU) was previously found to cause dose-dependent adrenal activation in the rat. The increased secretion of corticosterone (CORT) that results appeared to protect animals against HU toxicity, which was dramatically enhanced in adrenalectomized (ADX) rats. Similarities with the endocrine and toxicological profiles of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF) led us to suggest that these effects of HU might be mediated by an increased synthesis of these cytokines. The goal of this study was therefore to demonstrate that HU induces the gene expression and synthesis of proinflammatory cytokines in vivo. Intact and ADX rats were treated with HU, mRNA was extracted from spleen cells 2 and 24 hr after treatment and message levels for IL-1 alpha, IL-2, IL-4, IL-6, TNF alpha and interferon-gamma were evaluated using the reverse transcriptase-polymerase chain reaction technique. In some experiments, circulating levels of CORT and TNF were also measured. We found that transcripts of the proinflammatory cytokines, TNF, IL-6 and (though less clearly) IL-1 alpha, were expressed in the majority of intact rats treated with HU but were absent or less evident in most controls. In contrast, gene expression of IL-2, IL-4 and interferon-gamma was not influenced by drug treatment. Adrenalectomy markedly enhanced the effects of HU. Twenty-four hours after administration of the drug, the expression of TNF and IL-6 mRNAs was still higher in ADX rats compared with intact animals. Parallel measurements of plasma CORT levels revealed that gene expression of IL-1 alpha and, to a lesser extent, TNF was inversely related to levels of circulating CORT. Adrenalectomy per se caused a significant increase in plasma TNF levels compared with intact controls. Hydroxyurea elicited significant increases in circulating TNF in both ADX and intact rats. These findings lend support to our working hypothesis and provide an explanation for both the rise in glucocorticoid secretion induced by HU in intact rats and the increase in lethality observed in animals with disruptions of the hypothalamo-pituitary-adrenal axis.

Adrenalectomy↗

PubMed1977

In vivo synchronization of haemopoietic stem cells with hydroxyurea.

Four injections of hydroxyurea 1 mg/g body weight, given to normal mice 31, 24, 10 and 7 h before sampling bone marrow, reduced CFU-S content of femoral marrow to 30% of normal in Balb/c female and to 10% of normal in C57 B1 male mice. Over 80% of the surviving CFU-S were in the S phase of cycle, as judged from their sensitivity to killing by hydroxyurea or ARA-C.

Animals↗

PubMed1997

[Bilateral leg ulcers with pathologic evidence of small vessel vasculitis by skin biopsy during hydroxyurea therapy of chronic myelogenous leukemia].

We report a 45-year-old male with chronic myelogenous leukemia (CML) who experienced skin ulcers of the left lateral malleolus and dorsum of both feet. He had been treated with hydroxyurea (HU) for 2 years. His leg ulcers improved after HU was discontinued. Skin biopsy of the ulcerated lesion revealed that the lesion is compatible with small vessel vasculitis, but circulating immune complexes (C1q, anti-C3d antibody) were negative. Although the precise mechanism of the skin ulcer is unknown, we must take into consideration the skin changes were secondary to hydroxyurea therapy in myeloproliferative disorders.

Antineoplastic Agents↗

PubMed1997

Upregulation of interferon-alpha receptor expression in hydroxyurea-treated leukemia cell lines.

BACKGROUND: Interferon-alpha (IFN-alpha) shows its antitumor effect through binding to specific cell surface receptors. A DNA synthesis inhibitor, hydroxyurea (HU), has been successfully combined with IFN-alpha to improve the efficiency of IFN therapy for chronic myelogenous leukemia (CML). To understand the mechanism of this combination effect, expression of IFN-alpha receptors on the CML cell line, K562, was studied before and after treatment with HU. METHODS: Cells were treated with HU at a dose of 0, 0.1, 0.2, or 0.4 mmol/L for 48 hours. Binding assays were performed using 125I-labeled IFN-alpha at 4 degrees C. Cell cycle analysis was carried out using flow cytometer following staining cellular DNA with propidium iodide. Northern blot analysis was performed to evaluate the inducibility of interferon regulatory factor-1 (IRF-1) gene expression by IFN-alpha. RESULTS: Hydroxyurea-treated cells showed a dose- and time-dependent increase in binding of 125I-labeled IFN-alpha (maximal 2.5-fold). The increase of binding was caused by an increase in the number of binding sites with a constant receptor affinity. Similar results were obtained in the Burkitt's lymphoma cell line, Daudi. Cell cycle analyses suggested that upregulation of the IFN receptor may have occurred as a result of the alteration in the cell cycle distribution. Furthermore, IFN-alpha induction of the IFN-inducible gene IRF-1 mRNA in HU-treated K562 cells was 2-fold higher than that in untreated cells. CONCLUSIONS: Thus, HU may have an ability to enhance the response to IFN-alpha probably because of its ability to upregulate the IFN-alpha receptors, suggesting that this may be involved in the mechanism of effective combination therapy of IFN-alpha with HU.

Antineoplastic Agents↗

PubMedDate not supplied

Use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with hydroxyurea as post-transplant therapy in chronic myelogenous leukemia patients autografted with unmanipulated hematopoietic cells.

BACKGROUND AND OBJECTIVE: Allogeneic bone marrow transplantation remains the only potentially curative treatment for CML, but more than 70% of patients will be ineligible for allogeneic marrow transplant either because they do not have a suitable HLA-matched related or unrelated donor or because they are more than 50 years old. Several experimental and clinical findings support a role for autologous stem cell transplantation (ASCT) in CML. It has been suggested that in the early phase following autografting the Ph-negative clone has a proliferative advantage over the Ph-positive clone. We hypothesized that post-transplant GM-CSF administration could reactivate the functional activity of quiescent normal progenitors and prolong the duration of the post-transplant proliferative advantage of Ph-negative over Ph-positive progenitors. In order to evaluate the effect of post-transplant GM-CSF administration, a pilot clinical study was performed in which CML patients resistant to IFN-alpha therapy were autografted with unmanipulated marrow or blood cells and given prolonged GM-CSF therapy post-transplant. METHODS: Five adult CML patients conditioned with the BAVC regimen were reinfused with either marrow (n = 2) or blood (n = 3) cells and given granulocyte-macrophage colony-stimulating factor (GM-CSF). Recombinant GM-CSF was initially administered at standard dosage (5 micrograms/kg/day) until a white blood cell count > or = 2 x 10(9)/L was achieved on two consecutive examinations, and thereafter at a low dose (1 microgram/kg/day) for 5 to 9 months. On a weekly basis, GM-CSF was discontinued and hydroxyurea (1,000 mg/d) was given for two days. RESULTS: Evidence of trilineage engraftment was observed in all cases. At autografting, 3 out of the 5 patients revealed 8-9% Ph-negative metaphases. During the initial phase of hematopoietic regeneration, direct cytogenetic analysis revealed 81% and 100% Ph-negative metaphases in two cases; nonleukemic hematopoiesis progressively decreased and was no longer detectable at +9 months. One patient showed cyclic Ph-negative hematopoiesis that appeared 3 months following autografting and peaked at +4 and +8 months. The fourth patient showed a low percentage (20%) of Ph-negative metaphases 1 month after ASCT, followed by a significant expansion of nonleukemic hematopoiesis, which could be detected up to month +13. No evidence of Ph-negative hematopoiesis could be detected in one patient. Three patients are in chronic phase 28, 30 and 31 months after autografting, respectively, and two patients evolved into blast crisis. INTERPRETATION AND CONCLUSIONS: This pilot study demonstrates that combined GM-CSF and hydroxyurea therapy seems to be effective in inducing and/or prolonging a transient period of Ph-negative hematopoiesis. The late appearance of Ph-negative hematopoiesis detected in two patients suggests an antileukemic activity of the combined GM-CSF/hydroxyurea therapy rather than an antileukemic effect of the conditioning regimen.

Adult↗

PubMed1998

Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion.

Treatment with alkylating agents or radiophosphorous (32P) has been shown to carry a certain leukemogenic risk in myeloproliferative disorders (MPDs), including essential thrombocytemia (ET). The leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand, is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One or several therapeutic agents had been administered to 326 patients, including hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman in 43, busulfan in 41, and 32P in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and busulfan (one case). The incidence of AML and MDS after treatment, using 32P alone and 32P with other agents, busulfan alone and with other agents, HU alone and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful cytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosome 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and vacuoles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, as the only therapeutic agent in three, and followed by pipobroman in three. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenetic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated with a leukemic risk of approximately 3.5%. A high proportion of AML and MDS occurring in ET treated with HU (alone or possibly followed by pipobroman) have morphologic, cytogenetic, and molecular characteristics of the 17p- syndrome. These findings suggest that widespread and prolonged use of HU in ET may have to be reconsidered in some situations, such as asymptomatic ET.

Adult↗

PubMed1976

DTIC (nsc-45388) and combination therapy for melanoma. I. Studies with DTIC, BCNU (NSC-409962), CCNU (NSC-79037), vincristine (NSC-67574), and hydroxyurea (NSC-32065).

A total of 270 patients with metastatic malignant melanoma were entered into a randomized chemotherapy study conducted by the Central Oncology Group (COG) over a period of 2 years (COG protocol No. 7130). The study utilized DTIC, CCNU, BCNU, vincristine, and hydroxyurea. The results of therapy with DTIC alone were compared with three combinations: (a) DTIC, CCNU, and vincristine; (b) DTIC, BCNU, and vincristine: and (c) DTIC, BCNU, and hydroxyurea. There were 243 evaluable patients out of 270. The response rate was 17.3% (42 of 243 patients) for evaluable patients and 15.5% (42 of 270 patients) for all patients entered in the study. The results showed no statistically significant difference in the response rates among the four treatment arms. However, several significant points were observed: (a) A 13% response rate was obtained using a combination of agents that included DTIC in patients who had previously shown no response to DTIC used as a single agent. (b) There was a significant difference in survival time when comparing responders to those with no change and to those with progression. (c) Toxicity was noted to be greater in responders than in nonresponders. (d) Two of the four treatment arms were considered most advantageous due to the ease of administration. These treatment arms were DTIC, BCNU, and vincristine and DTIC, CCNU, and vincristine administered in 5-day courses every 6 weeks. (e) The percentage of response and length of survival were significantly greater in patients without brain or liver metastasis. (f) In comparing men to women there was no statistically significant difference in response in rates or durations of response. (g) There was no statistically significant difference in survival when comparing site of primary lesion.

Adolescent↗

PubMed1965

Hydroxyurea: differential lethal effects on cultured mammalian cells during the cell cycle.

Hydroxyurea has a differential lethal effect on cultured Chinesehamster cells that are at different stages in their cell cycle. Cells synthesizing DNA at the time of exposure to the drug are lethally damaged. Cells in the phase of growth preceding DNA synthesis (G(1)) survive but are prevented from beginning DNA synthesis. Cells in the phase after DNA synthesis (G(2)) survive and appear to progress until just before the beginning of the next period of DNA synthesis. This differential lethal and inhibitory effect of hydroxyurea may be useful for synchronizing asynchronous cell populations and explaining effects of the drug in human therapy.

Animals↗

PubMed1966

Effect of hydroxyurea on virus development. I. Electron microscopic study of the effect on the development of bacteriophage T4.

Margaretten, William (College of Physicians and Surgeons of Columbia University, New York, N.Y.), Councilman Morgan, Herbert S. Rosenkranz, and Harry M. Rose. Effect of hydroxyurea on virus development. I. Electron microscopic study of the effect on the development of bacteriophage T4. J. Bacteriol. 91:823-833. 1966.-Double fixation in gluteraldehyde and osmium tetroxide and the application of lead staining revealed details of viral structure not previously observed in thin sections. Bacteriophage presumed to have injected its deoxyribonucleic acid (DNA) exhibited a dense, hollow, disc-shaped core. Within the cytoplasm of infected bacteria, the peripheral membrane of the viral heads was clearly visible. Aberrant forms containing the hollow core and believed to be devoid of DNA were encountered in studies of the normal course of development. Hydroxyurea, which is believed to interfere with the production of infective bacteriophage by inhibiting DNA synthesis, resulted in the appearance of viral particles with the hollow disc or with bizarre, distorted cores. However, a significant number of viral heads looked entirely normal and presumably contained a full complement of DNA. Hypotheses are presented to explain these observations.

Coliphages↗

PubMed2026

Plasma Proteome Signatures in Sickle Cell Anemia and the Effect of Hydroxyurea Treatment.

Sickle Cell Anaemia (SCA) is a monogenic blood disorder caused by a mutation in the β-globin gene, yet it presents with marked clinical variability. Although hydroxyurea (HU) is an established therapy, its precise mechanism of action remains incompletely understood. Plasma proteins represent valuable biomarkers for elucidating disease mechanisms and treatment responses. In this study, plasma proteome profiling of 31 healthy controls and 76 SCA patients identified 43 differentially abundant proteins (DAPs) that form a highly interconnected interaction network. Proteins with increased abundance in SCA were largely associated with immune and inflammatory responses, whereas those with reduced levels were linked to coagulation and proteolytic pathways. HU therapy was associated with elevated levels of haptoglobin (HP) and hemopexin (HPX), key mediators of free hemoglobin scavenging. We also identified several previously unreported plasma proteins altered in SCA, broadening the landscape of potential biomarkers and HU-responsive targets. Many DAPs significantly correlated with clinical indices, such as transfusion frequency, vaso-occlusive crises, white blood cell counts, and platelet counts, offering insights into disease mechanisms and potential utility in disease management. Notably, overlap with β-thalassemia-associated signatures suggests shared pathophysiological pathways between these hemoglobinopathies. Collectively, these findings provide a strong foundation for translational validation in larger, independent cohorts.

Humans↗

PubMed2000

Long-term swallowing problems after organ preservation therapy with concomitant radiation therapy and intravenous hydroxyurea: initial results.

OBJECTIVE: To evaluate the long-term effects on swallowing function of concomitant continuous infusion hydroxyurea and hyperfractionated radiation therapy used to treat advanced head and neck carcinoma. DESIGN: A prospective evaluation of swallowing function was performed on an inception cohort by analyzing posttreatment videoflouroscopic swallow function studies using radiological descriptors for pharyngeal transport abnormalities and temporal measures of structural movements, as well as by conducting patient interviews to assess alimentation, more than 1 year after tumor treatment (range, 52-124 weeks; median, 70 weeks). SETTING: Academic tertiary care referral medical center. PATIENTS: Ten patients, aged 44 to 71 years, with stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, or hypopharynx. MAIN OUTCOME MEASURE: Radiographic and temporal swallow abnormalities, as well as functional status, were documented and compared with published norms and results of earlier swallowing studies when possible. RESULTS: Pharyngeal transport dysfunction and anterior segment abnormalities, manifested by epiglottic dysmotility, vallecular residue, laryngeal penetration, or aspiration, were evident in all 10 patients. Posterior segment abnormalities, such as pharyngeal stasis, constrictor dysmotility and piriform residue were documented in 8 patients. Three patients developed late aspiration, and the majority of patients showed persistent or worsened delay in laryngeal movement compared with their earlier posttreatment evaluations. Also, 3 patients developed a hypopharyngeal stricture, and 6 patients continued to require gastrostomy tube supplementation beyond 1 year. There was no association between site of primary, duration to swallowing evaluation, and severity of dysfunction. CONCLUSION: Prolonged and debilitating functional swallowing abnormalities may occur after this aggressive concomitant chemotherapy and radiotherapy regimen.

Adult↗

PubMed1996

Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

In polycythemia vera (PV), treatment with chlorambucil and radioactive phosphorus (p32) increases the risk of leukemic transformation from 1% to 13-14%. This risk has been estimated to be 1-5.9% with hydroxyurea (HU) therapy. When compared with historical controls, the risk with use of HU does not appear to be statistically significant. The leukemogenic risk of HU therapy in essential thrombocytosis (ET) and in myelofibrosis with myeloid metaplasia (MMM) is unknown. HU remains the main myelotoxic agent in the treatment of PV, ET, and MMM. We studied 64 patients with these three disorders, seen at our institution during 1993-1995. The patients were studied for their clinical characteristics at diagnosis, therapies received, and development of myelodysplasia or acute leukemia (MDS/AL). Forty-two had PV, 15 ET, and 6 MMM, and 1 had an unclassified myeloproliferative disorder. Of the 42 patients with PV, 18 were treated with phlebotomy alone, 16 with HU alone, 2 with p32, 2 with multiple myelotoxic agents, and 2 with interferon-alpha (IFN-alpha). Two patients from the phlebotomy-treated group, one from the HU-treated group, and 1 from the multiple myelotoxic agent-treated group developed MDS/AL. In the larger group, 11 received no treatment or aspirin alone, 18 were treated with phlebotomy alone, 25 with HU, 5 with multiple myelotoxic agents, 2 with p32, 2 with IFN-alpha, and 1 with melphalan. Study of the entire group of 64 patients showed that only one additional patient (total of 5 out of 64) developed MDS/AL. This patient had been treated with HU alone. Statistical analysis did not show any association between clinical characteristics at diagnosis, or HU therapy, and development of MDS/AL (P=0.5). Thus, our data provide no evidence suggestive of increased risk of transformation to MDS/AL with HU therapy in PV, ET, and MMM. Larger, prospective studies are needed to study this issue further.

Acute Disease↗

PubMed1999

Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia.

Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.

Adult↗

PubMed1997

Hydroxyurea-induced denaturation of normal and sickle cell hemoglobins in vitro.

Use of hydroxyurea (HU) to treat sickle cell disease is usually associated with increments in fetal hemoglobin (Hb F) production; however, in vitro studies show that HU may also induce hemoglobin denaturation. Whole blood samples from Hb AA, Hb AS, and Hb SS patients were treated in vitro with 100, 150, 200, 250, and 300 micrograms/mL HU, incubated at 30 degrees C for up to 12 days, and analyzed by high-performance liquid chromatography (HPLC). Hb AA levels show decrements of 91 to 14% with 100 micrograms/mL and 89 to 4% with 150 micrograms/mL after 12 days; 86 to 2% with 200 micrograms/mL after 10 days; 86 to 8% with 250 and 300 micrograms/mL after 8 days. Similar treatment and incubation times for Hb AS whole blood demonstrate that HU equally degrades the A and S components of Hb AS. A comparable approach for Hb SS whole blood samples, using a 300 micrograms/mL HU treatment, showed a hemoglobin denaturing pattern that went from 93% to 1% after 12 days. Globin chain analysis of these samples by reverse-phase HPLC showed that the denaturing effects occur mostly on the beta-globin chain.

Adolescent↗

PubMed2000

New NO donors with antithrombotic and vasodilating activities, Part 28. N-(1-cyanoalkyl)-N-hydroxyureas.

Nineteen N-(1-cyanoalkyl)-N-hydroxyureas comprising aliphatic (3a-i, 4a, b, and 5a) and aromatic (3j-n, 4c, 5b) compounds were prepared, fourteen of them for the first time, and tested for antithrombotic (p.o. administration to rats, 60 mg/kg) effects. The N-(1-cyanocyclohexyl)-N-hydroxy-N'-phenylurea (3j) was most potent and inhibited laser-induced (35 mW, 50 ms) thrombus formation in arterioles by 21% and that in venules by 15%. The compounds form nitric oxide in vitro by the addition of a Fe3(+)-porphyrin complex and an oxygen donor. Moreover, the most active compound 3j in vivo exhibits the highest NO formation in vitro. Furthermore, it was shown that the cyano group is essential for the desired activities and NO formation. These results suggest that the title compounds act as NO donors.

Animals↗

PubMed2000

Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors.

Hydroxyurea (HU) is a widely used cytotoxic agent that is known to induce fetal hemoglobin (HbF) production and is presently used to ameliorate the severity of pain episodes in patients with sickle cell anemia (HbSS). Previously we have shown that HU inhibits growth of burst forming unit-erythroid (BFU-E) colonies in a dose-dependent manner, while fetal hemoglobin levels were increased. In the present report, we extended our analysis demonstrating the number of S phase cells is significantly higher for HbSS patients that respond to HU therapy. Studies were completed in vitro using erythroid progenitors derived from umbilical cord samples or peripheral blood from patients with HbS-hereditary persistence of fetal hemoglobin (HbS-HPFH) or HbSS disease. The effect of HU on (a) S phase erythroid progenitors, (b) BFU-E colony growth, (c) HbF levels in BFU-E colonies, and (d) total cellular RNA synthesis was analyzed in vitro for the three groups. The level of S phase erythroid progenitors was similar for all three groups and BFU-E colony growth was inhibited 92-94% for all samples in a dose-dependent manner. The HbF levels were increased in BFU-E colonies from HbSS patients (control, 4.0% +/- 1.15% vs. +HU, 22.67% +/- 2.03%) whereas HbF levels were decreased in BFU-E colonies derived from umbilical cord samples (control, 80% +/- 9.07% vs. +HU, 35.7% +/- 4.81%) or HbS-HPFH patients (control, 49.67% +/- 3.84% vs. +HU, 23.3% +/- 0.88%). Total RNA synthesis measured by 3H-uridine incorporation increased with increasing concentrations of HU; however, actinomycin D inhibited HU-induced RNA synthesis. These results suggest that HU can inhibit an active globin gene without preference and that newly synthesized RNA is under transcriptional control mechanisms.

Adolescent↗

PubMed1978

Synergistic action of high-dose hydroxyurea when used with cyclophosphamide and certain new organoplatinum complexes in treatment of advanced L1210 leukemia.

Seven new organoplatinum (Pt) compounds, cyclophosphamide (CY), and hydroxyurea (HU) were used singly and in combination in treatment of advanced L1210 leukemia in C57BL/6 X DBA/2 mice. In each experiment the Pt + CY combination was supra-additive, as has been shown with other Pt compounds when used with CY. HU at the dose used (1000 mg/kg) was only minimally effective when used alone. However, six of the seven Pt + CY + HU combination regiments enhanced markedly the increased life span of treated mice when compared with the corresponding dual Pt + CY combination. The triple drug regimen yielded cure rates (760-day survival) up to 70% in individual experiments. Collectively, the cure rate was 11% with the various Pt + CY combinations, and was increased to 53% upon inclusion of HU in the regimen. It is suggested that HU may inhibit a process whereby potentially lethal DNA damage produced by Pt + CY would otherwise be repaired. A reduced efficacy of HU when used at a single, high-dose level was also noted, and a possible mechanism and potential significance of this observation are discussed.

Animals↗