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PubMed2005

Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial.

The recombinant urate oxidase, rasburicase (Elitek, Sanofi-Synthelabo, Inc.), has recently received regulatory approval for the prevention and treatment of hyperuricemia in children with leukemia, lymphoma, and solid tumors. Prior to approval, 682 children and 387 adults in the US and Canada received rasburicase on compassionate-use basis. Uric acid concentration declined rapidly in both adult and pediatric patients after rasburicase treatment. Similar responses were observed in patients treated with subsequent courses. Possible drug-related adverse events, including allergic reactions, were uncommon. These data confirm that rasburicase is effective and safe for the treatment and prophylaxis of children and adults with malignancy-associated hyperuricemia.

Adolescent↗
PubMed2000

Immunocytochemical localization of a urate oxidase immunoreactive protein in the plasma membranes and membranes of the secretory/endocytic compartments of digestive gland cells of the mussel Mytilus galloprovincialis.

The subcellular compartmentalization of urate oxidase (UOX) in the digestive glands of mussels, Mytilus galloprovincialis Lmk, was studied by means of immunoblotting and immunocytochemistry, using an antibody raised in rabbit against rat liver UOX. Western blot analysis of subcellular fractions revealed an immunoreactive polypeptide with a molecular weight similar to the corresponding mammalian hepatic protein. This crossreactive polypeptide of 32 kDa was particle-bound yet not peroxisome-associated. In paraffin sections the antiserum specifically labeled the plasma membrane of the digestive gland epithelial cells and discrete regions within the perinuclear and apical portions of the digestive tubules and duct cells. By electron microscopy gold particles representing antigenic sites were found on the microvilli and the lateral plasma membrane as well as the membranes of the secretory/ endocytic compartments, that is, the Golgi complex, secretory and some endocytic vesicle membranes. Since the peroxisomal UOX-antibody exhibits a comparable immunoreactivity towards a urate-transporter channel protein in rat kidney proximal tubules and has been used for its molecular cloning (Leal-Pinto et al., 1997, J. Biol. Chem. 272, 617-625), we suggest that the membrane protein identified in mussel digestive glands could represent a homologous urate-transporter protein.

Animals↗
PubMed2004

Identification, cloning and expression of Pseudomonas aeruginosa Ps-x putative urate oxidase gene in Escherichia coli.

In a previous study we reported for the first time the isolation and characterization ofurate oxidase enzyme from Pseudomonas aeruginosa. In this work we isolated and cloned a 1.350 kilobase DNA fragment that encode a putative urate oxidase gene from the genomic library of P. aeruginosa Ps-x. The nucleotide sequence of the cloned DNA insert revealed an open reading frame that encodes a protein of a molecular weight of 54.0 kDa. The cloned DNA fragment showed an uricolytic activity when expressed in E. coli DH5alpha. Surprisingly, the nucleotide sequence of the cloned gene showed more than 99% identity to the gene encoding hypothetical protein of P. aeruginosa PAO1. Moreover, the sequence of the cloned gene was closely similar to the corresponding uricase gene of Cellulomonas flavigena (44% similarity), but showed lower similarity values to that of Bacillus sp. BT-90 (24% similarity), Candida utilis (24% similarity). Interestingly, the isolated uricase gene showed closer similarity to uricase from yeast-like symbiotic fungi Beauveria bassiana (35%), Tolypocladium inflatum (29%), Paecilomyces tenuipes (27%) and Cerataphis fransseni (24%).

Amino Acid Sequence↗
PubMed2001

Recombinant urate oxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial.

To confirm the efficacy of recombinant urate oxidase (rasburicase) and to establish its safety profile, we reviewed the data on 173 children and 72 adults with malignancy who were treated with this new uricolytic agent in a compassionate-use trial. Rasburicase (0.20 mg/kg) was administered intravenously daily for 1 to 7 days and could be given every 12 h for the initial 72 h. Subsequent courses were allowed at a later date. Rasburicase produced a dramatic decrease in uric acid concentrations in all patients whether they received it for prophylaxis (n = 79) or treatment (n = 166) (P < 0.001 in all comparisons between the levels at diagnosis and those after treatment). The median post-treatment levels were 0.5 to 0.7 mg/dl. Repeated administrations were also effective in all 11 evaluable patients. Four children and five adults had mild adverse reactions that were drug related or of unknown etiology. In two of the children, the adverse events occurred during the second course. Rasburicase is highly effective and safe in the prophylaxis or treatment of malignancy- or chemotherapy-associated hyperuricemia in children and adults.

Adolescent↗
PubMed2006

Recombinant urate oxidase (rasburicase) for the prevention and treatment of tumor lysis syndrome in patients with hematologic malignancies.

In this multicenter, nonrandomized, open-label clinical trial conducted from July 2003 to July 2004, recombinant urate oxidase (rasburicase) was administered to patients at risk for tumor lysis syndrome before or during the initiation of chemotherapy. Forty-five patients were enrolled, including 18 children (10 with acute lymphoblastic leukemia, 6 with high-grade lymphoma, and 2 with acute myeloid leukemia) and 27 adults (8 with acute lymphoblastic leukemia, 4 with high-grade lymphoma, 9 with multiple myeloma, and 6 with acute myeloid leukemia). The age ranged from 3 to 98 years, with a median age of 7 years in children and 59.3 years in adults. There were 14 males and 4 females in the pediatric group and 18 males and 9 females in the adult group. Rasburicase 0.2 mg/kg was administered intravenously once a day for 2-6 days, for a median of 3 days in children and of 4 days in adults. After 3 days of treatment, the median uric acid levels in the 18 children decreased from 10.5 mg/dl (range 8-18.6) to 0.5 mg/dl (range 0.0-1.7). Similarly, in the 27 adults, the median levels decreased from 10.8 mg/dl (range 8-24.4) to 0.5 mg/dl (range 0.0-1.6). No significant changes were observed in serum potassium, calcium, and phosphorus concentrations. None of the patients required dialysis for acute renal failure. Rasburicase was very well tolerated, with only 1 adult having grade 1 vomiting. We conclude that rasburicase is safe and highly effective for preventing the complications of tumor lysis syndrome in patients with hematologic malignancies.

Adolescent↗
PubMed2001

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Adolescent↗
PubMed1993

An intraspecific gene duplication polymorphism of the urate oxidase gene of Drosophila virilis: a genetic and molecular analysis.

Nineteen strains of Drosophila virilis from diverse geographic locations were examined by genetic and molecular analyses, revealing (a) 12 strains with a single copy of the urate oxidase (UO) gene per haploid genome and (b) 7 strains with a tandem duplication of the UO locus. The D. virilis strains with the UO duplication appear to have identical restriction maps of this region, implying either a single origin for the duplication or several similar events occurring at a hot spot. On the basis of the location of the duplication breakpoints and the restriction sites flanking these breakpoints, this duplication probably arose through nonhomologous recombination involving either a breakage and rejoining event or replication slippage. because documented cases of intraspecific gene duplication polymorphism are rare, the D. virilis UO duplication will be useful in identifying the molecular event giving rise to a gene duplication.

Animals↗
PubMed1993

Sequence, regulation, and mutational analysis of the gene encoding urate oxidase in Aspergillus nidulans.

The uaZ gene of Aspergillus nidulans codes for a protein of 301 amino acids. The open reading frame is interrupted by two introns. A comparison with the open reading frames of 10 other urate oxidases reveals a number of scattered universally conserved residues and four clusters of high similarity. Two of these are of unknown function, and the other two are the putative sites for copper binding and the signal sequence for peroxisomal entry, respectively. This comparison also reveals that there are at 16 positions at which introns can be found in the gene coding for this enzyme in different species. The sequence of a number of mutations confirms the importance for enzyme activity of the carboxyl terminus of the protein. The most amino-terminal mutation (an ochre codon) results also in strikingly diminished steady-state levels of message. This agrees with results from other systems, suggesting that untranslated mRNA is preferentially degraded in eukaryotic cells. Northern blots show that specific induction, mediated by the UAY protein, and nitrogen metabolite repression, mediated by the AREA GATA factor, affect the steady-state levels of uaZ mRNA and thus act most probably at the level of transcription.

Alleles↗
PubMed2000

Aggregate formation and degradation of overexpressed wild-type and mutant urate oxidase proteins. Quality control of organelle-destined proteins by the endoplasmic reticulum.

To analyze the cellular response caused by the overexpression of proteins in subcellular compartments, we constructed four expression clones encoding wild-type peroxisomal urate oxidase (UO), truncated UO lacking the peroxisomal targeting signal (UOdC), and chimeric UOs with a mitochondrial targeting signal (MTS) at the N-terminus of UOdC (MUOdC) or UO (MUO). After transfection, we examined COS-1 and HEK293 cells by immunofluorescence and immunoelectron microscopy, transmission electron microscopy, and pulse-chase experiments. The overexpressed UO and UOdC formed large electron-dense aggregates with no limiting membrane in both the cytoplasm and the nucleus. The UO aggregates exhibited the crystalloid structure quite similar to that of rat liver peroxisomal cores, whereas the UOdC aggregates formed a loose mass consisting of small dense substructures. The overexpressed MUOdC and MUO, on the other hand, formed other types of aggregates which were distributed in the cytoplasm. They consisted of tubular and circular membrane structures, which were morphologically confirmed to be derived from the endoplasmic reticulum (ER). No immunolabeling signals for MUOdC and MUO were present free in the cytoplasm and most of them were associated with membrane structures, suggesting that overexpressed UO containing the MTS attached to the ER membranes soon after synthesis and segregated from the cytosolic compartment. All the UO aggregates were stained for ubiquitin antigen. Pulse-chase experiments in combination with proteasome inhibitors suggested that proteasomes did not contribute to the degradation of these products.

Animals↗
PubMed1991

Urate oxidase activity and copper content in the liver of macular mutant mouse, a model animal for human congenital copper deficiency, Menkes' kinky hair disease.

The macular mouse is an X-linked recessive inherited mutant and is considered to be a model for human congenital copper deficiency, Menkes' kinky hair disease. The activity of urate oxidase, which has been believed to be a copper enzyme, and copper content in the liver of the mutant mouse were determined. The oxidase activity was maintained at normal level even though there was very low level of copper present in the liver through days 7 to 14. Copper administration increased the copper content in the liver to the normal level, but did not affect the oxidase activity.

Animals↗
PubMed2006

Recombinant urate oxidase (Rasburicase) for the treatment of hyperuricemia in pediatric patients with hematologic malignancies: Results of a compassionate prospective multicenter study in Korea.

BACKGROUND: Hyperuricemia accompanying tumor lysis syndrome is a serious complication in neoplasia with rapid proliferation and destruction. To confirm the efficacy of recombinant urate oxidase (rasburicase) and its safety profile, a phase IV compassionate use prospective study was performed in Korean pediatric patients with hematologic malignancies. PROCEDURE: Rasburicase was administered at 0.2 mg/kg/day once daily for 3-5 days (twice daily allowed during the first 72 hr) by intravenous route for hyperuricemia (uric acid > 7.5 mg/dl). The study period was 5 weeks and consisted of a baseline assessment within 48 hr before the administration of rasburicase, 3-5 days of assessment during treatment and a follow-up assessment at 4 weeks after its final administration. RESULTS: The uric acid endpoint (< or =7.0 mg/dl) was reached in 97.3% (36/37) of the patients and uric acid levels were significantly reduced in all patients (P < 0.001). Drug related toxicities were mild and reversible without any grade 4 or serious adverse event associated with rasburicase. CONCLUSION: This study confirms that rasburicase is a safe and effective agent for the treatment of hyperuricemia associated with hematologic malignancies in pediatric patients.

Adolescent↗
PubMed2003

Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study.

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.(1) METHODS: A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (approximately 74%), lymphoma (approximately 24%), or solid tumors (approximately 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years). RESULTS: UA levels at 24-48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well tolerated. Serious adverse events related to rasburicase were observed in one patient. CONCLUSIONS: The results of the current study confirm that rasburicase is safe and highly effective in the prevention and treatment of chemotherapy-induced hyperuricemia in both children and adults.

Adolescent↗
PubMed2006

High-level expression, purification, and characterization of non-tagged Aspergillus flavus urate oxidase in Escherichia coli.

The entire encoding region for Aspergillus flavus uricase was cloned into pET-32a and expressed in Escherichia coli BL21 (DE3). The uricase was expressed in the E. coli cytoplasm in a completely soluble, biologically active form. A scalable process aimed to produce and purify multi-gram quantities of highly pure, recombinant urate oxidase (rUox) from E. coli was developed. The rUox protein was produced in a 30 L fermentor containing 25 L of 2x YT medium and purified to >99% purity using hydrophobic interaction, anion-exchange, and gel filtered chromatography. The final yield of purified rUox from fermentation resulted in approximately 27 g of highly pure, biologically active rUox per kg of cell paste (approximately 238 mg/8.8 g cell paste/L). The results presented here exhibit the ability to generate multi-gram quantities of rUox from E. coli that may be used for the development of pharmaceutics of reducing the hyperuricemia.

Aspergillus flavus↗
PubMed2003

Pan-European multicentre economic evaluation of recombinant urate oxidase (rasburicase) in prevention and treatment of hyperuricaemia and tumour lysis syndrome in haematological cancer patients.

GOALS: Hyperuricaemia (HU) and tumour lysis syndrome (TLS) are complications of acute myeloid/lymphoid leukaemia (AML/ALL) and non-Hodgkin lymphoma (NHL) leading to increased morbidity and mortality. The objective was to assess incremental cost-effectiveness ratios (ICER) of preventing/treating HU and TLS with recombinant urate oxidase, rasburicase (Fasturtec/Elitek). PATIENTS AND METHODS: Incidence and costs of HU and TLS were based on a multi-country chart review. Life expectancy at the time of diagnosis was based on published survival rates and age at diagnosis. Reductions of HU/TLS following treatment with rasburicase were based on clinical trial data. RESULTS: Prevention with rasburicase appears highly cost-effective in children (ICER between Eur 425 and Eur 3054 per life-year saved, LYS). In adults, prevention is more cost-effective in NHL and ALL (maximum ICER of Eur 41383 and Eur 32126 per LYS). Treatment of established HU/TLS with rasburicase is cost-saving in children and highly cost-effective in adults. The results are robust in children. In adults, the prevention strategy appears sensitive to the risk of HU/TLS. CONCLUSIONS: In conclusion, rasburicase, in addition to the demonstrated clinical benefit, is an economically attractive new option in the treatment of HU, both in adults and children. In prevention the drug has an attractive economic profile in children, and is cost-effective in adults with ALL and NHL.

Adult↗
PubMed2001

Mouse paracentric inversion In(3)55Rk mutates the urate oxidase gene.

The paracentric inversion In(3)55Rk on mouse Chromosome 3 (Chr 3) was induced by cesium irradiation. Genetic crosses indicate the proximal breakpoint cosegregates with D3Mit324 and D3Mit92; the distal breakpoint cosegregates with D3Mit127, D3Mit160, and D3Mit200. Giemsa-banded chromosomes show the inversion spans approximately 80% of Chr 3. The proximal breakpoint occurs within band 3A2, not 3B as reported previously; the distal breakpoint occurs within band 3H3. Mice homozygous for the inversion exhibit nephropathy indicative of uricase deficiency. Southern blot analyses of urate oxidase, Uox, show two RFLPs of genomic mutant DNA: an EcoRI site between exons 4-8 and a BamHI site 3' to exon 6. Mutant cDNA fails to amplify downstream of base 844 at the 3' end of exon 7. FISH analysis of chromosomes from inversion heterozygotes, using a cosmid clone containing genomic wild-type DNA for Uox exons 2-4, shows that a 5' segment of the mutated Uox allele on the inverted chromosome has been transposed from the distal breakpoint region to the proximal breakpoint region. Clinical, histopathological, and Northern analyses indicate that our radiation-induced mutation, uox(In), is a putative null.

Alleles↗
PubMed2003

Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study.

PURPOSE: Hyperuricemia and tumor lysis syndrome are well-known complications during induction treatment of aggressive non-Hodgkin's lymphomas (NHLs). Usual prophylaxis and treatment of hyperuricemia consist of hydration, alkalinization, and administration of allopurinol. This study was designed to evaluate the efficacy and the safety of rasburicase (recombinant urate oxidase) in adult patients with aggressive NHL during their first cycle of chemotherapy. PATIENTS AND METHODS: A total of 100 patients from Groupe d'Etude des Lymphomes de l'Adulte centers, with diffuse large B-cell lymphoma (n = 79); anaplastic large-cell lymphoma (n = 6); peripheral T-cell lymphoma (n = 8); transformation of indolent lymphoma (n = 5); Burkitt's lymphoma (n = 1); and lymphoblastic lymphoma (n = 1) were enrolled from May 2001 to June 2002. Before chemotherapy, 66% of patients had elevated lactate dehydrogenase (LDH), including 28% with LDH above 1,000 U/mL. Eleven percent of patients were hyperuricemic (uric acid [UA] > 450 mmol/L or > 7.56 mg/dL). Rasburicase 0.20 mg/kg/d intravenously for 3 to 7 days was started the day before or at day 1 of chemotherapy. UA levels were measured 4 hours after rasburicase injection, then daily during treatment. RESULTS: All patients responded to rasburicase, as defined by normalization of UA levels maintained during chemotherapy. The control of UA was obtained within 4 hours after the first injection of the drug. Creatinine levels and other metabolites were also controlled with the administration of rasburicase. No patient exhibited increased creatinine levels or required dialysis during chemotherapy. CONCLUSION: Rasburicase is the treatment of choice to control UA and prevent tumor lysis syndrome in adult patients with aggressive NHL.

Adult↗
PubMed2003

Recombinant urate oxidase for prevention of hyperuricemia and tumor lysis syndrome in lymphoid malignancies.

Hyperuricemia is a common manifestation of lymphoid malignancies at diagnosis or after the start of chemotherapy. When accompanied by other metabolic abnormalities and/or organ failure, hyperuricemia may be a manifestation of tumor lysis syndrome (TLS). Patients at particularly high risk of such complications include those with acute lymphoblastic leukemia and advanced stage non-Hodgkin's lymphoma. Conventional measures to prevent hyperuricemia and TLS are comprised of hydration, alkalinization of body fluids, and administration of allopurinol. Although these measures are usually effective in preventing or managing hyperuricemia, approximately 20% of patients at high risk of TLS require dialysis, and many cannot receive chemotherapy as planned. Rasburicase, a recombinant form of the enzyme urate oxidase, has recently become available and may further reduce the morbidity of hyperuricemia and TLS. In this review, we provide an overview of hyperuricemia and TLS and discuss the impact of rasburicase in the overall management of these complications.

Clinical Trials as Topic↗
PubMed2002

X-ray scattering studies of Aspergillus flavus urate oxidase: towards a better understanding of PEG effects on the crystallization of large proteins.

The determination of the three-dimensional structures of biological macromolecules by X-ray diffraction generally requires large good-quality crystals, which are often difficult to obtain as crystal nucleation and growth depend upon a great number of physicochemical parameters. In the future, the emergence of structural genomic projects will require new and rapid methods to determine crystallization conditions. Until now, the prediction of crystallization conditions has essentially been based on the knowledge of interparticular interactions in solutions inferred from studies on small soluble proteins in the presence of salts. The present study, by small-angle X-ray scattering, of urate oxidase from Aspergillus flavus, a homotetrameric enzyme of 128kDa, allowed the extension of the results to the crystallization of large proteins in the presence of polyethylene glycol (PEG). The protein crystallization, the nucleation rate and the different morphological crystal shapes obtained were correlated with the second virial coefficient (A(2)), which was found to be in a restricted range at the low end of the 'crystallization slot' proposed by George & Wilson [(1994). Acta Cryst. D50, 361--365].

Aspergillus flavus↗