Administration Of Hydroxyurea Research Articles

Spurious hypoxemia

To discuss the pathophysiology and clinical implications of spurious hypoxemia in the setting of hyperleukocytosis. Case report and review of the literature. A 22-bed, adult neurosciences critical care unit at a tertiary care hospital. A 49-yr-old male with chronic myelogenous leukemia. Administration of hydroxyurea and imatinib mesylate. The patient was admitted to the neurosciences critical care unit with an acute nontraumatic subdural hematoma that required emergent surgical evacuation. His clinical course was notable for neurologic deterioration, sepsis, hyperleukocytosis, severe hypoxemia, and prolonged mechanical ventilation. An inverse relationship was observed between arterial oxygen tension and the magnitude of hyperleukocytosis. Hypoxemia resolved after the institution of chemotherapy and normalization of white cell count. Pulse oximeter saturation was normal throughout. Patients with hyperleukocytosis are at risk for severe hypoxemia, which may be real or spurious. Failure to recognize spurious hypoxemia can lead to unnecessary diagnostic tests and therapeutic interventions, exposing patients to avoidable risk. A diagnostic algorithm is proposed.

A Case of Transition of Polycythemia Vera to Chronic Neutrophilic Leukemia

Chronic Neutrophilic Leukemia (CNL) is a rare myeloproliferative disorder characterized by a persistent increase of mature peripheral neutrophils, myeloid hyperplasia in bone marrow, hepatosplenomegaly, elevated neutrophil alkaline phosphatase (NAP) and absence of Philadelphia chromosome, with no evidence of infection or malignancy sufficient to mimic a leukemoid reaction. CNL has been associated with multiple myelomas in many reported cases, but transition of Polycythemia Vera (PV) to CNL is very rare.An 81-year-old female patient, who had undergone intermittent phlebotomy following the diagnosis of PV 8 years previously, was admitted to our hospital due to lower back pain. A physical examination showed a splenomegaly 2cm below the costal margin, with tenderness of the thoracic and lumbar spine area. A peripheral blood examination showed a WBC count of 91,800/μL (neutrophil 88%) with a rare immature form, hemoglobin of 9.1 g/dL and a platelet count of 1,661,000/μL. Her NAP score was 58. The bone marrow examination showed 95% cellularity, with an M:E ratio of 10:1, increased megakaryocytes with normal morphology and the absence of myelofibrosis. Chromosomal studies showed no Philadelphia chromosome. A radiological examination showed compression fractures of the vertebrae and spinal cord compression. No underlying disease causing a leukemoid reaction was detected. With iron replacement, the hemoglobin level failed to increase over 12 g/dL. Therefore, it was concluded to be a transition of PV to CNL. After administration of hydroxyurea and vertebroplasty, the symptom improved and the WBC count was sustained below 40,000/μL.

Global Gene Expression Profile of Human Bone Marrow before and after Hydroxyurea Administration in Sickle Cell Anemia.

The levels of HbF in sickle cell disease (SCD) can be increased by pharmacological agents such as hydroxyurea (HU), which has been shown to reduce the frequency of pain crises, hospitalizations and acute chest events requiring blood transfusions in adults with SCD. However, there is some evidence to suggest that some SCD patients show benefits from HU treatment without increase in their HbF levels. Thus, the molecular mechanism by which HU increases HbF levels and improves the clinical evolution in SCD remains unclear. This study aims to provide the global gene profile of human bone marrow of a homozygous patient three months before beginning treatment and after the initial administration of HU and to investigate groups of differentially expressed genes that could be involved in the pathways by which HU improves the clinical evolution in SCD. Using the Serial Analysis of Gene Expression (SAGE) technique, two libraries, before HU administration (HbS profile) and after HU administration (HbSHU) were performed. A total of 47.192 and 46.697 tags were analyzed for the HbS and HbSHU profiles and represented 15.735 and 15.901 distinct tags, respectively. Among these, 4.151 and 3.817 tags were no match tags that could represent new genes that remain to be identified. When both profiles were compared, 518 transcripts were determined to have statistically significant differential levels of expression (P value < 0.05). The functional annotation of transcripts, according to the Gene Ontology Consortium, showed that the categories of binding and structural molecule activity were up-regulated following HU treatment. For example, genes associated with nucleic acid binding such as Signal Transducer and Activator of Transcription 5 A, v-fos FBJ murine osteosarcoma viral oncogene homolog, Early Growth Response 1 and several ribosomal and zinc finger proteins were induced by HU treatment. Conversely, the transporter activity category was down regulated by HU treatment. Genes associated with oxygen transporter activity and other genes associated with ion binding, like S100 calcium binding protein A8 (calgranulin A) and transferrin were found to be down regulated by HU treatment. Taken together, these results strongly suggest that HU produces a significant change in the expression of bone marrow cells. Future studies of these described genes that are differentially expressed during HU treatment may contribute to further the understanding of the mechanism by which HbF acts in SCD and improves the clinical evolution of the disease. The description of new genes involved in these pathways may also represent a potential tool to identify new targets for the therapy of SCD.

Long Term Treatment with Hydroxyurea Does Not Prevent Development of Renal Dysfunction and Osteodystrophy in Patients with Sickle Cell Disease.

Hydroxyurea (HU) is presently considered as the main treatment for the reduction of sickle-cell crises; however, information regarding the potential of HU to inhibit progressive organ failure is scarce. The gradually failing renal function and renal osteodystrophy are well known complications of sickle cell disease (SCD). The pending question is whether administration of hydroxyurea over very long period of time may delay or prevent the appearance of these abnormalities. To this effect we evaluated the renal function and bone metabolism in 57 patients with HbS/β-thal (31M/26F; median age 32 years, range: 19–67 years) receiving hydroxyurea (usually 1 g/daily) continuously for 1 to 14 years (median 10.2 years). In addition to conventional renal biochemistry we measured the levels of serum and urinary β2-microglobulin (β2M), serum cystatin C (specific and sensitive index of glomerular filtration rate), and urine N-acetyl-b-D-glucosaminidase (NAG; reflecting the distal tubular cells function). The extent of renal osteodystrophy was evaluated by DEXA scans assessing bone mineral density (BMD), and by assaying various markers of (a) osteoclast function [soluble receptor activator of nuclear factor κB ligand (sRANKL), osteoprotegerin (OPG), and tartrate resistant acid phosphatase isoform 5b (TRACP-5b)], (b) bone resorption [C-telopeptide of collagen type I (CTX)], and (c) bone formation [bone-alkaline phosphatase (bALP) and osteocalcin (OC)]. The above parameters were also evaluated in 16 age- and gender-matched controls. Three patients (5.2%) had increased serum creatinine levels; 16 patients (28%) had more than 300 mg/day protein excretion in the urine, and 13 patients (22.8%) had microalbuminuria. Moreover, serum cystatin C was elevated in 16 patients (28%), NAG in 21 (36.8%), serum β2M in 34 (59.6%) and urinary β2M in one patient. In addition, 17 patients (29.8%) had osteoporosis/osteopenia in DEXA scans (comparable to HbS/β-thal patients who did not receive HU). Furthermore, all patients displayed significantly elevated levels of OPG (p=.001), sRANKL (p<.01), sRANKL/OPG ratio (p=.022), and CTX (p=.02), while significant correlations were found between serum cystatin C vs. both serum OPG and β2M levels as well as between cystatin C and the sRANKL/OPG ratio. Not only do these results suggest that HU does not prevent renal dysfunction in this cohort of patients but also highlight the role of RANKL/OPG pathway in the renal-induced bone disease of sickle cell syndromes. Furthermore, NAG, cystatin C and OPG may be useful as early biochemical markers for the assessment of renal impairment in SCD patients.

Oral squamous cell carcinoma during long-term treatment with hydroxyurea

Hydroxyurea (HU) is commonly used for the treatment of chronic myelogenous leukaemia, polycythemia vera and essential thrombocythaemia. Patients receiving HU present a number of side-effects including skin/mucosa changes and tumours. Mucocutaneous abnormalities include xerosis, ichthyosiform lesions, dark brown pigmentation of skin folds and nails, malleolar ulcers, oral mucositis and oral ulcers. Cutaneous squamous/basal cell carcinomas have also often been reported following long-term administration of HU. HU-induced carcinogenesis is due to both the mutagenic potential of this agent and to an impairment of DNA repair mechanisms after damage by external factors such as ultraviolet radiation. Oral cancer following long-term treatment with HU has been reported only once, in a patient with concomitant multiple skin tumours. We present the unique case of a patient with polycythemia vera who developed oral cancer after 15 years of HU therapy.

Traitement des méningiomes par hydroxyurée

Management of unresectable progressive meningioma remains controversial and constitutes a major challenge since therapeutic options including chemotherapy and hormone modulation are limited. Recent data have suggested that hydroxyurea treatment may have an antitumoral effect. The purpose of this prospective phase II study was to evaluate the efficacy of hydroxyurea treatment for unresectable progressive meningioma. From 1997 to 1999, consecutive patients presenting unresectable meningioma with clinically and/or neuroradiologically documented progression were considered for entry into this protocol. Previous radiotherapy was not a mandatory inclusion criteria. Treatment consisted of continuous oral administration of hydroxyurea at a dose of 20 mg/kg per day. Follow-up assessment included physical examination, computed tomography (CT), and magnetic resonance imaging (MRI) performed every three months, as well as regular blood testing. The primary endpoint was documentation of objective response by MRI or CT. The intent-to-treat population was 43 patients with at least 18 months follow-up. Median age was 60.4 years. Twenty-eight patients had undergone surgery following initial diagnosis. The meningioma was located in the skull base in 67% of patients. Histology was benign in 18 and atypical in 10. The eligible population included 36 patients with documented progressive disease at the time of inclusion; with progression documented clinically in 29 (67.5%) and/or radiologically in 20 (46%). In 7 patients, clinical or radiological progression could not be confirmed. The intent-to-treat analysis at median 26 months follow-up revealed objective response to hydroxyurea in only 3 patients (7%) including one on the basis of improvement in visual symptoms and two on MRI analysis. Progressive disease was observed clinically or radiologically in 26 patients (60.5%). Of the eligible population (n=36), 2 achieved an objective response and 13 (36%) exhibited stabilization under hydroxyurea therapy, while 21 (58%) progressed under treatment. Overall tolerance was good but anemia (grade I-II) and asthenia (grade I-II) were observed in 28% and 23.5% respectively. Treatment was discontinued in 3 patients because of chronic skin toxicity in one and anemia and asthenia in two. Hydroxyurea treatment is of marginal efficacy for meningioma and must not be considered as an alternative if radiotherapy or surgery is feasible. New efficient medical treatments are still required for progressive meningiomas.

303. Impaired Nuclear Transport and Virus Uncoating Limit Recombinant Adeno-Associated Virus 2 Vector-Mediated Transduction of Primary Murine Hematopoietic Cells

The transduction efficiency of adeno-associated virus 2 (AAV) vectors varies greatly in different cells and tissues. Whereas muscle and brain cells are transduced efficiently, controversies abound regarding hematopoietic cell transduction by AAV vectors. For human hematopoietic cells, we documented this problem to be related to the extent of AAV receptor expression (J. Virol., 71: 8262–8267, 1997). Murine hematopoietic cells express the receptor, yet are transduced poorly. Using a murine fibroblast cell line, we reported that the lack of transduction was due to inefficient intracellular trafficking of AAV from cytosol into the nucleus (J. Virol., 74: 992–996, 2000), and that treatment with hydroxyurea (HU) facilitated nuclear transport of AAV in these cells (J. Virol., 75: 4080–4090, 2001). In the present studies, we extended these observations to primitive murine hematopoietic cells. Murine c-kit+, lin− hematopoietic cells were transduced with recombinant AAV-lacZ vectors. Forty-eight hrs. post-transduction, nuclear and cytoplasmic fractions were isolated and low Mr DNA samples extracted from these fractions were analyzed on Southern blots. Approximately 85% of AAV genomes were present in the cytoplasmic fraction. However, when donor mice were injected intra-peritoneally with HU at 1 mg/g body weight, 24 hrs. prior to isolation of cells, the extent of AAV genomes detected in the cytoplasmic fraction was reduced to ~40%, with a corresponding increase in the nuclear fraction, which increased to ~60%, indicating that in vivo administration of HU facilitated nuclear transport of AAV. However, when DNA samples were electrophoresed on denaturing gels and analyzed on Southern blots, it was apparent that a significant fraction of the AAV genome present in the nuclear fraction from cells obtained from HU-treated mice was single-stranded. We tested the hypothesis whether single-stranded genomes were derived from virions that failed to undergo uncoating in the nucleus. Primitive hematopoietic cells, with and without HU-administration in vivo, were transduced with recombinant AAV-lacZ vectors, and 48-hrs. post-transduction, equivalent fractions were either mock-treated, or digested exhaustively with DNase I, and analyzed on DNA slot-blots using a lacZ probe. Whereas majority of the signal, which was resistant to DNase I, was detected in the cytoplasmic fraction in cells obtained from untreated mice, as expected, a substantial fraction of the signal in the nuclear fraction in cells obtained from HU-treated mice was also resistant to DNase I, suggesting that although HU facilitated nuclear transport of AAV, most of the virions failed to undergo uncoating, thereby leading to only a partial improvement in viral second-strand DNA synthesis and transgene expression. Thus, the identification of a yet another obstacle — virus uncoating — has implications in the optimal use of recombinant AAV vectors in hematopoietic stem cell gene therapy.

Growth-suppression effect of hydroxyurea on meningioma cells in vitro

To investigate the tumor-suppression effect of hydroxyurea on meningioma cells and its possible mechanism. The meningioma cells were cultured in medium containing varied doses of hydroxyurea (5x10(-3)mol/L, 5x10(-4)mol/L, 5x10(-5)mol/L), the cell growth was measured by MTT method, cell apoptosis was observed with flow cytometry (FCM). MTT measurement demonstrated that the administration of hydroxyurea led to a dose-dependent suppression in cell proliferation and FCM showed a dose-dependent increase in apoptosis rate. Hydroxyurea can inhibit meningioma cell growth in vitro, which is most likely associated with apoptosis of the tumor cells.

Safety profile of long term administration of low dose hydroxyurea in thalassemia intermedia

Background Hydroxyurea therapy in thalassemia intermedia is an off-label use of this drug. We conducted a retrospective study to determine the safety profile of low dose hydroxyurea in patient with thalassemia intermedia. Methods: We interviewed patients who were 5.5 to 39 years old. A total of 133 patients with thalassemia intermedia were interviewed in person with the use of a questionnaire that incorporated classified adverse reaction of hydroxyurea by organ system. We obtained detailed information about blood counts, liver and renal function test from patients records. Results: The duration of hydroxyurea therapy was between 6 months to 54 months. The mean dose of hydroxyurea was 10.74 mg/kg/day. Use of hydroxyurea was not associated with serious adverse effects. 89 of the 133 patients (66.9%) did not show any identifiable adverse reaction. Among the remainder, the most common unwanted effects was headache (12%) followed by skin pigmentation (7.5%), hair loss (6%), maculo-papular rash (6%), dizziness (5.25%), anorexia (4.5%), facial erythema (3.25%), nausea and vomiting (1.3%). The rate of discontinuation was zero. All of the adverse reactions were mild, transient and well tolerated. Bone marrow suppression and/or secondary malignancies were not developed in any patient. Conclusions: Hydroxyurea was well tolerated in patients with thalassemia intermedia with minimal adverse reactions. Clinical Pharmacology & Therapeutics (2004) 75, P58–P58; doi: 10.1016/j.clpt.2003.11.222

Plasma Levels of TNF- in Sickle Cell Patients Receiving Hydroxyurea

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-) from human macrophages in vitro and the concentration of TNF- is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF- and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF- and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF- was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF- in the StSt group was not significantly different than in the VOC group; however, the plasma TNF- tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF- (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-. These findings suggest that a HU-induced increase in TNF- does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF- does not counteract the beneficial effects of HU in SCD.

Neutrophils and neutrophil products do not mediate pulmonary hemodynamic effects of endotoxin on oleic acid-induced lung injury.

Small-dose endotoxin (Etx) prevents pulmonary perfusion redistribution away from edematous dorsal lung regions after oleic acid (OA)-induced injury in dogs, causing a significant deterioration in oxygenation. We hypothesized that small-dose Etx might mediate this effect via polymorphonuclear neutrophil (PMN) priming with release of inflammatory mediators such as platelet activating factor (PAF) or secretory phospholipase A(2) (sPLA(2)). To test this hypothesis, we administered specific inhibitors directed against each mediator and used two strategies to generate neutropenia. PAF and sPLA(2) inhibitors were administered before OA injury, followed 2 h later by small-dose Etx (n = 4 each group). PMN depletion was achieved by hydroxyurea administration for 5 days before the study to achieve absolute neutrophil counts <1000/mm(3) (n = 4). Inhibition of PMN adherence to lung endothelium was achieved by the administration of an anti-CD18 monoclonal antibody immediately before lung injury (n = 5). Positron emission tomography was used to evaluate pulmonary perfusion distribution and lung water content. We observed no effect of these interventions on the perfusion pattern after Etx + OA. Thus, neither neutrophils nor PAF or sPLA(2) mediate the effects of Etx on the pattern of perfusion in this model of lung injury. Acute respiratory failure is characterized by severe decreases in blood oxygen. The pattern of blood flow within the lungs can contribute to this problem. This study investigated the potential role of white blood cells and their products in mediating abnormal pulmonary blood flow patterns in an experimental animal model of respiratory failure.

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Effect of fetal hemoglobin-stimulating medicines on the interaction of DNA and protein of important erythroid regulatory elements.

Beta-Thalassemia is the most common single gene disorder in the world, which is caused by the imbalance between alpha-globin chain and beta-globin chain synthesis. Several medicines, such as 5-azacytidine, hydroxyurea, cytarabine, vinblatine, butyrate, and myleran, have been shown to be able to reactivate gamma-globin chain synthesis during the adult stage, and some of them (5-azacytidine, hydroxyurea, myleran, and butyrate) have been used clinically to treat thalassemia and sickle cell disease. Much research efforts are focusing on the determination of the underlying mechanisms of medicine action. In this experiment, as an effort to probe the underlying mechanism of medicine action, we used ligation-mediated polymerase chain reaction and in vivo footprinting methods to study the DNA-protein interaction at critical erythroid regulatory elements after hydroxyurea or myleran administration to mice. Our results showed that the patterns of in vivo footprints at both the hypersensitive site 2 of the locus control region and the beta-globin gene promoter were changed after medicine treatment. We proposed based on these results that the medicines' administration might result in a change in the interaction between trans-acting factors and cis-acting elements at these regions. These changes might influence the assembly of the transcription complex and, lastly, influence the expression of the beta-globin gene.

The Nitric Oxide Producing Reactions of Hydroxyurea

Hydroxyurea is used to treat a variety of cancers and sickle cell disease. Despite this widespread use, a complete mechanistic understanding of the beneficial actions of this compound remains to be understood. Hydroxyurea inhibits ribonucleotide reductase and increases the levels of fetal hemoglobin, which explains a portion of the effects of this drug. Administration of hydroxyurea to patients results in a significant increase in levels of iron nitrosyl hemoglobin, nitrite and nitrate suggesting the in vivo metabolism of hydroxyurea to nitric oxide. Formation of nitric oxide from hydroxyurea may explain a portion of the observed effects of hydroxyurea treatment. At the present, the mechanism or mechanisms of nitric oxide release, the identity of the in vivo oxidant and the site of metabolism remain to be identified. Chemical oxidation of hydroxyurea produces nitric oxide and nitroxyl, the one-electron reduced form of nitric oxide. These oxidative pathways generally proceed through the nitroxide radical (2) or C-nitrosoformamide (3). Biological oxidants, including both iron and copper containing enzymes and proteins, also convert hydroxyurea to nitric oxide or its decomposition products in vitro and these reactions also occur through these intermediates. A number of other reactions of hydroxyurea including the reaction with ribonucleotide reductase and irradiation demonstrate the potential to release nitric oxide and should be further investigated. Gaining an understanding of the metabolism of hydroxyurea to nitric oxide will provide valuable information towards the treatment of these disorders and may lead to the development of better therapeutic agents.

Vascular Events Associated with Alpha Interferon Therapy

Alpha Interferon (IFN) is a biological agent used for the therapy of an increasing number of diseases, either as an established effective therapeutic tool or in the context of clinical trials. The use of IFN may be complicated by serious adverse reactions. We describe here the clinical course of a variety of vasculopathic complications in association with IFN-therapy in 12 patients with the diagnosis of chronic myeloid leukemia and 1 patient with malignant melanoma treated at our institute. Vascular manifestations in these patients include Raynaud's phenomena, digital ulcerations and gangrene, pulmonary vasculitis, pulmonary hypertension and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). These reactions occurred after 3 months to 3 years of 3-10 million units (MU) daily IFN therapy. Concomitant administration of hydroxyurea (HU) was noted in 5 patients. Discontinuation of IFN and initiation of immunosuppressive therapy brought about a complete resolution or arrested progression of these reactions. IFN-therapy may be complicated by severe vasculopathic/vasospastic complications that usually improve after its discontinuation. Possible underlying mechanisms for these complications are discussed. The early diagnosis of these complications may be vital and IFN should be immediately discontinued when early signs of these complications become evident.

Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea.

Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration. Our data showed that chronic HU significantly increased NO, cGMP, and HbF levels in SCD. Recently it was shown that HbF production was stimulated by cGMP-dependent protein kinase. Our results suggest that NO stimulates cGMP production, which then activates a protein kinase and increases the production of HbF.

Chronic myeloid leukaemia with marked thrombocytosis in a patient with thalassaemia major: complete haematological remission under the combination of hydroxyurea and anagrelide

The co-existence of thalassaemia major and chronic myeloid leukaemia (CML) is a very rare event. We report a 32-year-old man with thalassaemia major whose progressively increasing leukocytosis and thrombocytosis led to the diagnosis of CML confirmed by the characteristic t(9;22)(q34;q11) chromosomal translocation and the bcr-abl (b3a2) DNA fusion. The patient was treated with hydroxyurea and anagrelide. This combination resulted in the satisfactory control of both the white blood cell and platelet counts, which has continued over the past 14 months with no major side-effects, albeit with no molecular response. The administration of hydroxyurea was also associated with a significant HbF increase.

Gene Expression Profiling in Chronic Myeloid Leukemia Patients Treated with Hydroxyurea

Using array technology that allows the simultaneous detection of gene expression of hundreds of genes, four patients with chronic myeloid leukemia (CML) were investigated at diagnosis and after starting administration of hydroxyurea. To detect the gene expression of peripheral blood mononuclears and granulocytes Human Cancer cDNA Array (CLONTECH) with 588 gene probes was used. Gene expression mononuclear and granulocyte profiles of patients at diagnosis were compared with the control profiles. The significant expression changes observed in most patients seemed to be important. Increased expression of c-jun N-terminal kinase 2 (JNK2), integrin alpha E, MMP-8, MMP-9 was detected in both fractions of most patients. In some samples PCNA, HDGF, MAPK p38, CD59 increased expressions were found. Significant down-regulation of expression in patients was detected in genes CDK4 inhibitor A, PURA, notch1 in mononuclears; STAT2, STAT5, RAR-alpha, MCL-1, junB, caspase 4 in granulocytes; CDK6, GADD153, ERBB-3, cadherin 5 in both fractions. Expression profiles detected in patients at diagnosis did not differ markedly from those after one-week treatment with hydroxyurea. Only in a few genes were significant changes after hydroxyurea administration observed and inter-individual expression differences were rather common.

Optimisation of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of hydroxyurea, leucovorin, 5-FU and cisplatin (HLFP regimen) for metastatic oesophageal cancer

To improve the efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in metastatic esophageal cancer, we designed a new therapeutic schedule, the HLFP regimen. 42 patients with metastatic oesophageal adenocarcinoma (n=10) or squamous cell carcinoma (n=32) were prospectively enrolled in the study. All had bidimensionally measurable disease. The HLFP regimen consisted of twice-monthly oral administration of hydroxyurea 1 g/m2 on days 0, 1 and 2; a 2-h infusion of leucovorin 200 mg/m2 and a bolus of 5-FU 400 mg/m2 followed by a 22-h infusion of 5-FU 600 mg/m2 on days 1 and 2; and, every two cycles, 80 mg/m2 cisplatin on day 3. Relief of dysphagia and other symptoms were monitored, together with body weight changes. Major objective responses were observed in 24 patients (57%, 95% Confidence Interval (CI): 42–72%), including four complete responses (10%). The median progression-free survival and overall survival times were 8 and 12.7 months, respectively. Weight gain was observed in 48% of patients, and dysphagia improved in 76%. Grade 3-4 toxicity occurred in 40% of patients, with grade 4 neutropenia in 12% and grade 3 thrombocytopenia, vomiting and diarrhoea in 7–9% of patients. There were no treatment-related deaths. These results suggest that the HLFP regimen is an active and well-tolerated chemotherapy for metastatic oesophageal carcinoma.

Increased erythropoietin level induced by hydroxyurea treatment of sickle cell patients.

Administration of hydroxyurea in sickle cell disease is associated with a dramatic increase of HbF along with a significant clinical improvement and, occasionally, increased total hemoglobin levels. The underlying mechanisms are not yet fully elucidated. We report the response of three patients with homozygous sickle cell disease and 10 patients with compound HbS/beta-thalassemia (four with beta(o)thal/HbS and six with beta(+)thal/HbS respectively) to hydroxyurea treatment with regards to their serum erythropoietin levels (sEpo). Baseline sEpo levels varied from 33.0 to 284.0 IU/L and showed a significant negative correlation with the respective Hb values (P<0.007). Two to three weeks after initiation of treatment, the sEpo values started to increase and reached levels three to 31 times higher than the baseline two to three weeks later. Thereafter, in most cases the Epo values decreased and remained at intermediate levels throughout the rest of hydroxyurea administration, while in a few cases, they returned to baseline. An inappropriate increase of sEpo following treatment with various cytostatic drugs, independently of anemia induced by cytostatic agents, has already been reported in the literature. The cytostatics included cyclophosphamide, anthracyclines, cytosine arabinoside etc., but not hydroxyurea. The results described here with hydroxyurea are virtually similar, ie, they show a significant sEpo increase five to ten days post therapy with no apparent cause. Pulses of high dose Epo have been reported to promote proliferation of erythroid precursors with HbF synthesizing capacity. Our hypothesis is that a similar phenomenon may occur here also, in the sense that peaks of endogenous Epo may promote proliferation of erythroid precursors which maintain the capacity to synthesize HbF.