Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper is concerned with the evaluation of the in vivo performance characteristics of reconstituted bovine collagen as an insoluble carrier matrix fro therapeutic enzymes. The enzyme that was chosen as a model for this evaluation was E. coli L-asparaginase, which has been widely investigated as a soluble chemotherapeutic agent for the treatment of acute lymphocytic leukemia in humans (Oettgen et al., Cancer Res., 27, 2619, 1967 ; Beard et al., Brit. Med. J., 1, 191, 1970; Ohmuma et al., Cancer Res., 30, 2297, 1970). The results presented here were obtained from perfusion trials with a collagen-asparaginase reactor incorporated into an extracorporeal circuit attached to the vascular systems of healthy mongrel dogs. A series of 1-2 hr perfusions were conducted with a single collagen-asparaginase membrane over a period of 4 months. Serum asparagine levels were reduced by more than 98% after 15-30 min perfusion time. Red blood cell (RBC), hemoglobin, hematocrit, and fibrinogen values remained constant during each perfusion. An average decrease of 48% in white blood cell (WBC) and 24% in platelet levels was observed, but these values began to rise slowly even before cessation of the perfusion. No serious toxic or antigenic reactions or mechanical or clotting difficulties were observed. In vitro activity, when assayed between perfusions, remained constant over a period of 4 months of intermittent use and storage. The potential advantages of collagen-enzyme complexes for the administration of therapeutic enzymes is discussed.
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PMID:Perfusion trials with a collagen-immobilized enzyme in an extracorporeal reactor: activity, stability, and biocompatibility. 84 82

A 71-year-old female was diagnosed as hypoplastic leukemia (ALL, L 2). Vitamin D3 (D3) therapy with alfacalcidol was successful and remission continued for approximately 4 months. However, the leukemia became refractory to D3, and low dose Ara-C combined with D3 was ineffective. Combined chemotherapy with vincristine, cyclophosphamide, L-asparaginase and prednisolone, low dose aclarubicin, OK-432 and etretinate ended in a failure. Treatment with mepitiostane was started and 1 month later obvious elevation of hemoglobin concentration, white cell and platelet count was observed. A bone marrow aspirate showed distinct recovery of normal hemopoiesis without residual leukemic cells. The patient has been staying in the complete remission for over 15 months with mepitiostane therapy (30 mg, daily). Androgen therapy, such as mepitiostane, appears to be effective in some patients with hypoplastic leukemia which does not indicate intensive chemotherapy.
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PMID:[Complete remission by mepitiostane in hypoplastic leukemia]. 268 84

The patient was an eight-year-old black male who presented to the Children's Hospital of Philadelphia (CHP) in June 1977 with foot pain. Abnormal findings on physical examination were diffuse shotty lymphadenopathy without hepatosplenomegaly. Examination of the extremities was normal. There was no evidence of increased bruising or bleeding. Laboratory data revealed a hemoglobin of 11.2 gm/dl, white blood cell count of 26,200/cu mm, and platelet count of 21,000/cu mm. Serum uric acid level was 4.2 mg/dl. The remainder of the laboratory findings were within normal limits. Bone marrow examination revealed a hypercellular marrow replaced with lymphoblasts. Immunologic evaluation showed these cells to have no surface immunoglobin and no rosette formation with sheep red blood cells. The patient received vincristine 1.5 mg/M2 daily, oral prednisone at 40 mg/M2 daily, L-asparaginase 6,000 IU/M2 for nine intramuscular doses, and methotrexate 12 mg intrathecally. After 28 days, bone marrow aspiration showed that the leukemia was in remission. He then received 2,400 rad cranial irradiation over three weeks, along with four more doses of intrathecal methotrexate, given once weekly. Maintenance consisted of monthly pulses of vincristine (1.5 mg/M2), prednisone (40 mg/M2 for five days), daily oral 6-mercaptopurine (75 mg/M2), and weekly oral methotrexate (20 mg/M2). After six months of maintenance, the patient was given a scheduled course of reinduction therapy with vincristine, prednisone, and L-asparaginase. Eleven months after diagnosis both testes were noted to be enlarged on physical examination. Wedge biopsy of both testes revealed leukemic infiltration. Examination of the bone marrow and cerebrospinal fluid (CSF) at that time were unremarkable. The patient was treated with vincristine, prednisone, and L-asparaginase again for four weeks and received intrathecal methotrexate as central-nervous-system (CNS) prophylaxis. Twenty-four hundred rad were given to both testes at 200 rad/day with decrease in testicular size. Maintenance consisted of monthly pulses of vincristine and prednisone with oral methotrexate and 6-mercaptopurine. Seven months after his testicular relapse the patient had a bone marrow relapse. He expired eight months later with disseminated leukemia.
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PMID:Proceedings of the tumor board of the Children's Hospital of Philadelphia. Testicular leukemia: incidence and management results. 694 80

The use of polymers for delivering peptide and protein drugs is described. Soluble-polymer technology attempts to bind a polymer to all sites on therapeutic protein molecules that cause the body to recognize the molecules as foreign. Goals include a stable linkage, water solubility, low immunogenicity, prolonged half-life, and intact biological activity. Polyethylene glycol (PEG)-adenosine deaminase (ADA), or pegademase bovine, has FDA-approved labeling as replacement therapy for ADA deficiency in patients with severe combined immunodeficiency disease who are not suitable candidates for bone marrow transplantation. Pegademase bovine reverses the toxic accumulation of adenosine and deoxyadenosine in adenosine deaminase-deficient cells, restoring the immune system. PEG-asparaginase (pegaspargase) has shown promise in patients with acute lymphocytic leukemia; allergic reactions have been minimal. Animal studies suggest that superoxide dismutase has potential use in conditions in which the body's ability to remove oxygen free radicals is reduced, such as burns and myocardial infarction; coupling with PEG may greatly increase the protein's half-life. Other PEG-conjugated proteins under investigation include PEG-catalase, PEG-uricase, PEG-honeybee venom, PEG-hemoglobin, and PEG-modified ragweed pollen extract. Dextran, albumin, DL-amino acids, and polyvinyl pyrrolidone have also been studied as protein carriers; most of the products created thus far have not shown much promise. The coupling of polymers to proteins has yielded protein drugs with intact biological activity and reduced immunogenicity, but much remains to be learned about this technology.
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PMID:Polymers for delivering peptides and proteins. 816 Jun 72

Hyperglycemia in children with acute lymphoblastic leukemia (ALL) has been well documented in the literature. The purpose of the present study was to evaluate the clinical value of glycated hemoglobin (GHb) and fructosamine (Frc) in the long-term glycemic control of ALL patients. An attempt was made to identify the risk factors for hyperglycemia in ALL patients. The study group comprised 26 newly diagnosed ALL patients admitted to hospital during 1995-96. Patients with a history of blood transfusion or infection within the past 3 months were excluded from the study. White blood cell (WBC) counts, fasting blood glucose (FBG), GHb and Frc levels were analyzed in venous blood on screening day 0, before induction of chemotherapy. Frc analysis was repeated on the 21st day and GHb level on the 60th day of chemotherapy. FBG tests were performed before each dose of L-asparaginase, on days 21 and 60. None of the patients was obese. Although six children (23%) had hyperglycemia during the induction therapy, four of them had a GHb level higher than normal on admission. Only one patient who developed hyperglycemia had a family history of diabetes mellitus. Patients with a high initial WBC count (> 20 x 10(9)/L) had a significantly higher baseline GHb than patients with a WBC count below this level. GHb values returned to normal after achievement of complete remission. It is suggested that the leukemic process could impair glucose metabolism and baseline GHb may be used to monitor possible small changes in glucose homeostasis of ALL patients, prior to chemotherapy.
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PMID:Clinical value of glycated hemoglobin and fructosamine in the long-term glycemic control of children with acute lymphoblastic leukemia. 958 1

The prognostic value of immunophenotype in adult acute lymphoblastic leukemia (ALL) has varied based on the methods used, surface markers studied, and therapy administered. From April 1991 to September 1996, samples of leukemic marrow or blood from 259 eligible and evaluable adult ALL patients entering dose-intensive Cancer and Leukemia Group B (CALGB) front-line treatment protocols were prospectively studied for immunophenotypic classification by multiparameter flow cytometry (MFC) in a central laboratory. A B-lineage (B-LIN) phenotype was expressed in 79% of cases, with one third coexpressing myeloid antigens. A T-lineage (T-LIN) phenotype was expressed in 17% of cases, with one quarter coexpressing myeloid antigens. Since the advent of more intensive CALGB therapy which incorporated cyclophosphamide and the early use of L-asparaginase into the backbone of daunorubicin, vincristine and prednisone, together with central nervous system prophylaxis for adult ALL, no significant differences in response rates, remission duration, or survival have been seen in those patients coexpressing myeloid antigens. The T-LIN phenotype was associated with younger age (P =.01), a higher male to female ratio (P =.01), higher white blood cell count (P =.001) and hemoglobin (P <.001) levels, presence of a mediastinal mass (P <. 001), and longer survival (P =.01) and disease-free survival (DFS) (P =.01) when compared to patients with a B-LIN phenotype. The 3-year probability of survival and DFS (95% confidence interval [CI]) of T-LIN adult ALL was 0.62 (0.46 to 0.76) and 0.62 (0.44 to 0. 77), respectively. Comparatively, the 3-year probability of survival and DFS (95% CI) of B-LIN adult ALL was 0.42 (0.35 to 0.50) and 0.39 (0.31 to 0.47), respectively. The number of T markers expressed in T-LIN ALL cases was shown to have prognostic significance. In particular, patients expressing six or more markers compared with patients expressing three or fewer markers had longer DFS (P =.003) and survival (P =.004). The presence of the Philadelphia chromosome was significantly associated with B-LIN ALL cases which coexpressed CD19(+), CD34(+), and CD10(+) (49%; P =.003), whereas the majority of t(4;11) cases were CD19(+), CD34(+) but CD10(-). The knowledge gained from this study of MFC of a large number of patients will permit a reduction in the number of antigens to be evaluated in future studies. Overall, this should lead to cost savings without loss of valuable information. A rational approach for future studies would be to use four-color flow cytometry (instead of the current three-color) to help further streamline the study of immunophenotype of adult ALL by MFC.
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PMID:Value of immunophenotype in intensively treated adult acute lymphoblastic leukemia: cancer and leukemia Group B study 8364. 1033 2

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.
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PMID:Bioconjugation in pharmaceutical chemistry. 1051 Aug 47

A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure.
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PMID:Toxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole. 1097 34

The acute lymphoblastic leukemia cell line CCRF-CEM is sensitive to Ara-C and undergoes apoptosis. In contrast, the chronic myelogenous leukemia (CML) cell line K562 is highly resistant to Ara-C, which causes the cells to differentiate into erythrocytes before undergoing apoptosis. We used cDNA microarrays to monitor the alterations in gene expression in these two cell lines under conditions leading to apoptosis or differentiation. Ara-C-treated CCRF-CEM cells were characterized by a cluster of down-regulated chaperone genes, whereas Ara-C-treated K562 cells were characterized by a cluster of up-regulated hemoglobin genes. In K562 cells, Ara-C treatment induced significant down-regulation of the asparagine synthetase gene, which is involved in resistance to L-asparaginase. Sequential treatment with Ara-C and L-asparaginase had a synergistic effect on the inhibition of K562 cell growth, and combination therapy with these two anticancer agents may prove effective in the treatment of CML, which cannot be cured by either drug alone.
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PMID:cDNA microarray analysis of altered gene expression in Ara-C-treated leukemia cells. 1295 Oct 57

This study is the first utilizing Vitreoscilla hemoglobin in a heterologous bacterium, Enterobacter aerogenes, to determine the effect of such a highly efficient oxygen-uptake system on the production of l-asparaginase, an enzyme that has attracted considerable attention due to its anti-tumor activity. Here, we show that the Vitreoscilla hemoglobin expressing strain has from 10-fold to more than two orders of magnitude lower l-asparaginase activity than the wild type or the control without the Vitreoscilla hemoglobin gene under different aeration conditions. Aeration and agitation were also determining factors for enzyme production. The enzyme activity was reduced considerably under both full aerobic and anaerobic conditions, while the highest enzyme activity was determined in cultures under low aeration and low agitation. Also, the effect of different concentrations of glucose on enzyme production showed catabolic repression. Glucose at 1% caused almost total inhibition of enzyme activity, while at 0.1% it showed a slightly stimulatory effect on enzyme production, compared with glucose-free medium.
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PMID:Production of L-asparaginase in Enterobacter aerogenes expressing Vitreoscilla hemoglobin for efficient oxygen uptake. 1459 9


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