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PubMed1982

The effect of isoproterenol and hydroxyurea on the presence of ubiquitin and protein A24 in the rat salivary gland.

The in vivo administration of hydroxyurea for 12 h counteracts DNA synthesis and cell cycling stimulated by 72 h of isoproterenol treatment in rat salivary gland, as determined by fluorescence-activated flow cytometry. Hydroxyurea has little effect on [3H]leucine incorporation (protein synthesis) of the nuclear proteins soluble in 0.35 M NaCl, when examined by polyacrylamide gel chromatography and autoradiography from electrostatically sorted nuclei of (G0 + G1) and (G2 + M) phases of the in vivo cell cycle. Differential incorporation of [3H]leucine into nuclear proteins was observed during various phases of the cell cycle. Proteins 'X' and 'Z', observed in stained gel chromatographs of the 0.35 M NaCl-soluble nuclear proteins, were identified by biochemical analyses as ubiquitin and protein A24, respectively. Ubiquitin appeared transiently while A24 increased in gel chromatograms concomitant with progressive quiescence of the salivary gland induced by hydroxyurea.

Amino Acids↗

PubMed1996

Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer.

We tested paclitaxel (Taxol) and low dose hydroxyurea as second line therapy in 30 patients with non-small cell lung cancer since both drugs are active against non-small cell lung cancer in other settings, and since hydroxyurea may reverse chemotherapy resistance by disrupting double minute chromosomes. Hydroxyurea 500 mg was given orally each Monday, Wednesday, Friday starting 1 week before paclitaxel, and continuing until removal from study. Paclitaxel 135 mg/m2 was given i.v. over > or = 1 h every 3 weeks with dexamethasone, diphenhydramine, and ranitidine. Patients could have paclitaxel doses escalated to 175 mg/m2 in course 2 and to 200 mg/m2 in course 3, where tolerated. Sixteen males and 14 females were treated. All patients had previously received a single cisplatin-based chemotherapy regimen and 23 had previously received radiotherapy. Twelve patients had adenocarcinomas, six had squamous cell carcinomas, and 12 had large cell carcinomas. Eight patients had Stage IIIb cancers and 22 had Stage IV. Paclitaxel doses were 135 mg/m2 in 56 courses, 175 mg/m2 in 24, and 200 mg/m2 in 15. Treatment was well tolerated. Median granulocyte nadirs were 2.5 (x 10(9)/l) for paclitaxel 135 mg/m2, 1.8 for 175 mg/m2, and 1.3 for 200 mg/m2. No patient developed febrile neutropenia, and none required a dose reduction. Two patients had reversible anaphylaxis. Other toxicities were quite tolerable. They included fatigue, myalgias, dizziness, paresthesias, diarrhea, alopecia, mucositis, flushing, headache, swollen red hands, and anxiety. One patient had a partial remission and 15 had stable disease (including six with minor responses). Median survival was 20 (95% CI, 12-34) weeks, with 19% of patients remaining alive at 1 year from initiation of treatment. This is a well-tolerated regimen with modest activity as second line chemotherapy for patients with non-small cell lung cancer previously treated with cisplatin regimens. Higher doses would be feasible and other strategies are now being explored.

Aged↗

PubMed1991

Hydroxyurea therapy.

Hydroxyurea's place in the scheme of psoriasis therapy has diminished in recent years. Some practitioners mistakenly believe that it is used only in desperate situations, is of little or no benefit in patients unresponsive to more conventional systemic therapies, and may predispose patients to the development of secondary malignancies. Moreover, a legitimate argument against the use of this drug may be made by physicians concerned about the proliferation of systemic therapies for what is a benign, albeit unsightly, eruption. However, hydroxyurea therapy is not without advantages. It is easily dosed, relatively inexpensive, and has few contraindications or subjective side effects. In addition, patients with common systemic disorders such as hyperlipidemia, mild renal insufficiency, and cardiopulmonary disease who may not be potential candidates for other medications may be managed with hydroxyurea.

Humans↗

PubMed1987

Actions of insulin on MCF-7 cells that are synchronized with hydroxyurea.

The role of insulin in stimulating metabolic processes in MCF-7 cells was studied in cells synchronized at the G1:S interphase of the cell cycle using hydroxyurea. Cells released from the hydroxyurea block progressed through one S-phase of the cell cycle when insulin was absent from the medium. When free insulin was present the cells continued through more than one S-phase. Since cells accumulate at G0 in serum- and hormone-free conditions it is apparent that insulin has an essential action in the MCF-7 cells between the G0 and S-phase of the cell cycle. Insulin is also known to stimulate the incorporation of [3H]leucine into a pH 4.6 precipitable phosphoprotein fraction in the MCF-7 cells. Insulin was shown to express this action, even when the cells were maintained at the G1:S interphase with hydroxyurea. Insulin is thus able to effect a differentiative action, i.e. a stimulation of phosphoprotein synthesis, under conditions where insulin's effect on [3H]thymidine incorporation into DNA is prevented.

Cell Cycle↗

PubMed1980

Synthesis of DNA in human fibroblasts treated with T-2 toxin and HT-2 toxin (the trichothecene metabolites of Fusarium species) and the effects of hydroxyurea.

(1) 3alpha-Hydroxy-4beta, 15-diacetoxy-8alpha-(3-methylbutyryloxy)-12,13-epoxytrichothec-9-ene (T-2 toxin) and HT-2 toxin both inhibited the incorporation of tritiated thymidine into the DNA of human fibroblasts; the inhibition was dose-related. (2) The presence of hydroxyurea (HU) did not affect unscheduled DNA synthesis in human fibroblasts damaged by T-2 toxin (0.006 mug/ml to 20.0 mug/ml) or by HT-2 toxin (0.032 mug/ml to 100.0 mug/ml) as with cycloheximide. (3) In the presence of the rat-liver microsomal fraction, S-9 and of hydroxyurea, there was an increase in unscheduled DNA synthesis in human fibroblasts exposed to 100 mug/ml of HT-2 toxin. (4) Thus in the presence of the microsomal S-9 fraction and of hydroxyurea the effect of HT-2 toxin (at 100 mug/ml) appeared to resemble that of benzo(a)pyrene: further studies are needed to clarify the ròle of its derivatives in the mechanism of action of T-2 toxin.

DNA↗

PubMed1993

Deoxyguanosine reverses inhibition by hydroxyurea of repair of UV-irradiated adenovirus 5.

Hydroxyurea, an inhibitor of ribonucleotide reductase, blocks the repair by normal human fibroblasts of ultraviolet light-damaged adenovirus 5. A mixture of all four DNA deoxynucleosides present with hydroxyurea reversed the inhibition, an effect consistent with the target of hydroxyurea being ribonucleotide reductase. Single deoxynucleosides were differentially effective in reversing the inhibition: deoxyguanosine reversed 100% of the HU block, deoxyadenosine 70%, deoxythymidine 55%, but deoxycytidine only 3%. The results are interpreted in the context of the known pattern of stimulation and inhibition of mammalian ribonucleotide reductase by dNTP effectors. We suggest that biological data may be important to assessing the availability of substrate for the ribonucleotide reductase molecules that provide dNTPs for DNA repair.

Adenoviridae↗

PubMed2006

N-hydroxyurea--a versatile zinc binding function in the design of metalloenzyme inhibitors.

N-Hydroxyurea binds both to carbonic anhydrase (CA) and to matrix metalloproteinases (MMPs). X-ray crystallography showed N-hydroxyurea to bind in a bidentate mode by means of the oxygen and nitrogen atoms of the NHOH moiety to the Zn(II) ion of CA, participating in a network of hydrogen bonds with a water molecule and Thr199. A derivatized N-hydroxyurea showed low-micromolar affinity for several CAs. This simple zinc binding function may be exploited for obtaining potent metalloenzyme inhibitors, due to its versatility of binding to the metal ion present in the active site of such enzymes.

Binding Sites↗

PubMed2005

Centrosome amplification induced by hydroxyurea leads to aneuploidy in pRB deficient human and mouse fibroblasts.

Alterations in the number and/or morphology of centrosomes are frequently observed in human tumours. However, it is still debated if a direct link between supernumerary centrosomes and tumorigenesis exists and if centrosome amplification could directly cause aneuploidy. Here, we report that hydroxyurea treatment induced centrosome amplification in both human fibroblasts expressing the HPV16 -E6-E7 oncoproteins, which act principally by targeting p53 and pRB, respectively, and in conditional pRB deficient mouse fibroblasts. Following hydroxyurea removal both normal and p53 deficient human fibroblasts arrested. On the contrary pRB deficient fibroblasts entered the cell cycle generating aneuploid cells. Also the majority of conditional Rb deficient MEFs showed supernumerary centrosomes and aneuploid cells which increased over time. Finally, our results suggest that pRB dysfunction both in human and murine fibroblasts transiently arrested in G1/S by hydroxyurea allows centrosomes amplification, in the absence of DNA synthesis, that in turn could drive aneuploidy.

Aneuploidy↗

PubMed2004

Hydroxyurea-associated squamous dysplasia.

We report 2 cases of squamous dysplasia associated with long-term hydroxyurea therapy. The association between hydroxyurea and multiple aggressive squamous cell carcinomas, Bowen's disease, and multiple actinic keratoses in sun-exposed areas after a variable latency period has been increasingly reported. On reviewing the literature, 17 cases were identified and are reviewed, with emphasis on possible pathogenetic mechanisms of carcinogenicity. Squamous dysplasia, a precursor state to a more aggressive condition of multiple squamous cell carcinomas in photoexposed areas, should be added to the well-known cutaneous toxicities of hydroxyurea therapy.

Aged↗

PubMed2000

[Secondary cutaneous effects of hydroxyurea: prospective study of 26 patients from a dermatologic consultation].

PURPOSE: Hydroxyurea is a treatment of myeloproliferative syndromes. Its cutaneous side-effects are underestimated, because they are usually benign. We undertook a prospective study to evaluate their frequency. METHODS: During a 2-year period, all patients taking hydroxyurea for more than 6 months who had consultations at the dermatology department were systematically examined, regarding cutaneous side effects. RESULTS: Twenty-six patients were examined. All but one had cutaneous side-effects, including dryness (n = 16), moderate alopecia (n = 2), increased skin pigmentation (n = 5), melanonychia, single (n = 1) or multiple (n = 7), cutaneous atrophy (n = 4), leg ulcers (n = 8), plantar keratoderma (n = 3), pseudodermatomyositis (n = 1), lichen planus-like eruption on the dorsum of the hands (n = 2), actinic keratosis (n = 8), squamous cell carcinomas (n = 2), and mouth ulcerations (n = 1). CONCLUSION: This study shows that the frequency of hydroxyurea cutaneous side-effects diagnosed in 95% of studied patients is underestimated. They are usually benign, but some of them, in particular leg ulcers and squamous cell carcinomas, lead to modification of the treatment (39% of studied patients).

Antineoplastic Agents↗

PubMed1997

Fever attributed to the use of hydroxyurea.

We report on three patients who developed fever after starting treatment with the anti-neoplastic agent, hydroxyurea. Fever occurred within 5 days to 3 weeks after starting treatment. In all cases the causal relationship between fever and use of hydroxyurea was demonstrated by spontaneous recovery after drug withdrawal and was confirmed by recurrence of fever after rechallenge. Other causes were excluded. Fever was accompanied by rash, gastro-intestinal and pulmonary symptoms, and arthralgia. Physicians should be aware of the fact that unexplained fever may be caused by hydroxyurea.

Aged↗

PubMed1998

Time resolved absorption study of the reaction of hydroxyurea with sickle cell hemoglobin.

Hydroxyurea has been mixed with hemoglobin S and the reaction was studied using electronic absorption spectroscopy as a function of time and wavelength. The rate of conversion of oxyhemoglobin S to other species was determined and the nature of the reaction products was studied. We also report the formation of methemoglobin (and other reaction products) when deoxyhemoglobin S is combined with hydroxyurea. The probable increase in the formation of methemoglobin, and other potential reaction products such as nitric oxide-hemoglobin, in patients with sickle cell anemia who are taking hydroxyurea as a therapeutic drug is discussed in terms of the pathophysiology of the disease. It is proposed that methemoglobin and possibly nitric oxide-hemoglobin formation may partially explain beneficial effects observed in these patients before their levels of fetal hemoglobin have increased.

Anemia, Sickle Cell↗

PubMed2000

Senescence-like changes induced by hydroxyurea in human diploid fibroblasts.

Hydroxyurea was found to inhibit the growth of human diploid fibroblasts, which resulted in senescence-like changes both in morphology and replicative potential similar to the replicative senescence. SA-beta-gal activity, a typical characteristic of the replicative senescence was also induced through a long-term treatment of the presenescent cells with 400-800 microgM of hydroxyurea for about 3 weeks. In addition, we determined the levels of cyclin-dependent kinase inhibitors, p21(Waf1) and p16(INK4a), and the p53 tumor suppressor in order to monitor its effect on cell cycle and stress responses. We observed a great induction of both p53 and p21(Waf1), but not of p16(INK4a) in the premature senescent cells. UV-irradiation of the premature senescent cells showed a decreased level of DNA fragmentation presumably ascribed to the reduced activation of stress-activated protein kinases. These results suggest that a chronic hydroxyurea treatment induces the cellular senescence in association with the induction of p53 and p21(Waf1).

Cells, Cultured↗

PubMed1977

Effect of the solvent-dependent conformational system of hydroxyureas on predicted vs. observed log P.

Calculated and observed log P values are reported and compared with in vivo and in vitro biological action (L1210 leukemia ILS % and ribonucleotide reductase ID50) for hydroxyurea, the 1-N methyl and ethyl, and the 3-N ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, and p-chlorophenyl analogues. The log P values were calculated via the method of Hansch and Leo from literature f values and the observed log P values were obtained by direct determination after equilibration between octanol and water. Calculations of log P for hydroxyurea were found to be appreciably more hydrophilic than the values obtained experimentally. Differences in calculated and observed log P (delta log P) for the substituted analogues were lowest with the 1-N and the bulky 3-N substituents and greatest with the 3-N-substituted straight-chain analogues (delta log P = 0.70). Different structural species were observed by infrared spectroscopy in dry octanol vs. octanol after water equilibration and drying, and this is proposed as due to changes in conformational equilibrium in the hydroxyurea systems. Differences between calculated and observed log P are explained via the stabilization of internally hydrogen-bonded conformers in the case of 1-N or bulky 3-N analogues or destabilization of various conformers allowing maximal interactions with solvent or water which is the case with straight chain 3-N analogues.

Chemical Phenomena↗

PubMed2005

The novel L- and D-amino acid derivatives of hydroxyurea and hydantoins: synthesis, X-ray crystal structure study, and cytostatic and antiviral activity evaluations.

The novel L- and D-amino acid derivatives of hydroxyurea 5a-o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a-o with hydroxylamine. The hydantoin derivatives 6a-e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among L-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC(50) = 10-19 microM) and showed selectivity with respect to normal human fibroblasts (WI 38). d-Amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC(50) = 4.8-83.9 microM), but not the growth of normal fibroblasts (WI 38; IC(50) > 100 microM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC(50) = 3.2 microg/mL; 6m, EC(50) = 4.0 microg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC(50) = 43.4 microg/mL; 6m, CC(50) = 12.5 microg/mL(-1)).

Amino Acids↗

PubMed1992

Analysis of hydroxyurea in capsules and aqueous solution and stability study with capillary gas chromatography and thermionic (N-P) specific detection.

A method for the analysis of hydroxyurea (HU) in solutions, powder, or capsules by use of capillary gas chromatography with N-P thermionic specific detection is described. Upon injection of an HU solution in a methanol and acetone mixture, the drug formed pyridine which was well separated from the internal standard (thiotepa) on a 30-m fused-silica, SE-30 capillary column with temperature programming. The peak height ratio versus concentration standard curves were linear with correlation coefficient ranging between 0.9942 and 0.9993. The coefficients of variation at 5, 25, and 50 micrograms/L were 7.2, 5.7, and 5.5%, respectively. Hydroxyurea was extracted from powder or capsule formulations with a mixture of methanol and acetone (50:50, v:v), and the percentage found of the label claim for 10 capsules ranged between 96.7 and 104.9 (mean = 100.1; CV = 2.7%). Further, this assay was used to examine the stability of hydroxyurea in aqueous solutions at 4, 23, and 45 degrees C, and the apparent first-order rate constants observed at these temperatures were 0.06407, 0.08113, and 0.1293 day-1, respectively; the activation energy was 3011 cal.K-1.mol-1.

Calibration↗

PubMed2000

Hydroxyurea chemotherapy for unresectable or residual meningioma.

Meningiomas represent 18-20% of all intracranial tumors and have a 10-year recurrence rate of 20-50%, despite aggressive surgery and irradiation. In addition, many tumors are not amenable to surgery due to their deep location or proximity to delicate structures. Chemotherapy is being explored as another potential treatment option for unresectable or refractory meningiomas. Hydroxyurea is an agent that inhibits ribonucleotide reductase and can induce apoptosis in meningioma cell cultures and animal models. We have placed 17 patients with unresectable or residual meningioma on hydroxyurea chemotherapy (20 mg/kg/d orally). The mean age of our cohort was 57.2 years; 13 patients were female. Eleven patients had actively growing tumors or neurological progression at the onset of chemotherapy. Sixteen patients were evaluable for response. Fourteen of the 16 patients (88%) responded with stable disease ranging from 20 to 144+ weeks (median 80 weeks; 10 patients still accruing time). Three of the responders progressed after 20, 36, and 56 weeks, respectively. Two patients had progressive disease after 10 weeks. Toxicity was hematologic in most patients; leukopenia was most common. Nine patients (53%) required dosage reductions (250-500 mg/d) secondary to hematologic toxicity. Hydroxyurea appears to have modest activity against meningiomas and should be considered in patients with unresectable tumors or large residual tumors following surgical resection.

Adult↗

PubMedDate not supplied

Non-resectable slow-growing meningiomas treated by hydroxyurea.

PURPOSE: To test the benefit of hydroxyurea in the treatment of recurrent and non-resectable slow-growing meningiomas. METHODS: Twelve patients with regrowing non-malignant meningiomas, were enrolled for a protocol of 2 years with continuous chemotherapy with hydroxyurea, 20 mg/kg/day. Response to treatment was evaluated both clinically and by diagnostic imaging using computed tomography (CT) and 201-Thallium single photon emission CT. One minimal response was documented by CT, accompanied by clinical stabilization. Nine patients showed progressive disease, at least by one imaging procedure, with a median time to progression of 13 months (range 4-24). Two other patients were not available for response due to early removal from the study, following abrupt manifestation of grades 3-4 hematological toxicity. CONCLUSION: In this series hydroxyurea has not shown effectiveness in the treatment of non-resectable slow-growing meningiomas: neither for achieving response, nor for arresting disease progression.

Adult↗