UMLS:C0023418 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asparagine synthetase catalyzes the ATP-dependent formation of L-asparagine from L-aspartate and L-glutamine, via a beta-aspartyl-AMP intermediate. Since interfering with this enzyme activity might be useful for treating leukemia and solid tumors, we have sought small-molecule inhibitors of Escherichia coli asparagine synthetase B (AS-B) as a model system for the human enzyme. Prior work showed that L-cysteine sulfinic acid competitively inhibits this enzyme by interfering with L-aspartate binding. Here, we demonstrate that cysteine sulfinic acid is also a partial substrate for E. coli asparagine synthetase, acting as a nucleophile to form the sulfur analogue of beta-aspartyl-AMP, which is subsequently hydrolyzed back to cysteine sulfinic acid and AMP in a futile cycle. While cysteine sulfinic acid did not itself constitute a clinically useful inhibitor of asparagine synthetase B, these results suggested that replacing this linkage by a more stable analogue might lead to a more potent inhibitor. A sulfoximine reported recently by Koizumi et al. as a competitive inhibitor of the ammonia-dependent E. coli asparagine synthetase A (AS-A) [Koizumi, M., Hiratake, J., Nakatsu, T., Kato, H., and Oda, J. (1999) J. Am. Chem. Soc. 121, 5799-5800] can be regarded as such a species. We found that this sulfoximine also inhibited AS-B, effectively irreversibly. Unlike either the cysteine sulfinic acid interaction with AS-B or the sulfoximine interaction with AS-A, only AS-B productively engaged in asparagine synthesis could be inactivated by the sulfoximine; free enzyme was unaffected even after extended incubation with the sulfoximine. Taken together, these results support the notion that sulfur-containing analogues of aspartate can serve as platforms for developing useful inhibitors of AS-B.
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PMID:Characterization of inhibitors acting at the synthetase site of Escherichia coli asparagine synthetase B. 1155 Dec 15

System L is a major nutrient transport system responsible for the transport of large neutral amino acids including several essential amino acids. We previously identified a transporter (L-type amino acid transporter 1: LAT1) subserving system L in C6 rat glioma cells and demonstrated that LAT1 requires 4F2 heavy chain (4F2hc) for its functional expression. Since its oncofetal expression was suggested in the rat liver, it has been proposed that LAT1 plays a critical role in cell growth and proliferation. In the present study, we have examined the function of human LAT1 (hLAT1) and its expression in human tissues and tumor cell lines. When expressed in Xenopus oocytes with human 4F2hc (h4F2hc), hLAT1 transports large neutral amino acids with high affinity (K(m)= approximately 15- approximately 50 microM) and L-glutamine and L-asparagine with low affinity (K(m)= approximately 1.5- approximately 2 mM). hLAT1 also transports D-amino acids such as D-leucine and D-phenylalanine. In addition, we show that hLAT1 accepts an amino acid-related anti-cancer agent melphalan. When loaded intracellularly, L-leucine and L-glutamine but not L-alanine are effluxed by extracellular substrates, confirming that hLAT1 mediates an amino acid exchange. hLAT1 mRNA is highly expressed in the human fetal liver, bone marrow, placenta, testis and brain. We have found that, while all the tumor cell lines examined express hLAT1 messages, the expression of h4F2hc is varied particularly in leukemia cell lines. In Western blot analysis, hLAT1 and h4F2hc have been confirmed to be linked to each other via a disulfide bond in T24 human bladder carcinoma cells. Finally, in in vitro translation, we show that hLAT1 is not a glycosylated protein even though an N-glycosylation site has been predicted in its extracellular loop, consistent with the property of the classical 4F2 light chain. The properties of the hLAT1/h4F2hc complex would support the roles of this transporter in providing cells with essential amino acids for cell growth and cellular responses, and in distributing amino acid-related compounds.
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PMID:Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. 1155 28

Cell shrinkage and loss of cell viability by apoptosis have been examined in cultured CD95(Fas/Apo-1)-expressing leukemia-derived CEM and HL-60 cells subjected to acute deprivation of glutamine, a major compatible osmolyte engaged in cell volume control. Glutamine deprivation-mediated cell shrinkage promoted a ligand-independent activation of the CD95-mediated apoptotic pathway. Cell transfection with plasmids expressing FADD-DN or v-Flip viral proteins pointed to a functional clustering of CD95 receptors at the cell surface with activation of the 'extrinsic pathway' caspase cascade. Accordingly, cell shrinkage did not induce apoptosis in CD95 receptor-negative lymphoma L1210 cells. Replacement of glutamine with surrogate compatible osmolytes counteracted cell volume decrement and protected the CD95-expressing cells from apoptosis. A glutamine deprivation-dependent cell shrinkage with activation of the CD95-mediated pathway was also observed when asparaginase was added to the medium. Asparagine depletion had no role in this process. The cell-size shrinkage-dependent apoptosis induced by glutamine restriction in CD95-expressing leukemic cells may therefore be of clinical relevance in amidohydrolase enzyme therapies.
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PMID:Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis. 1159 98

Asparaginase comes from different biological sources and the various preparations have different pharmacokinetic properties, and their tendency to induce side-effects is different. Erwinia asparaginase (ASNase) has a shorter half-life than the Escherichia coli preparations, and it has been reported to be less immunogenic than the E. coli preparations and to induce fewer coagulation disorders. Children with newly diagnosed acute lymphoblastic leukaemia (ALL) were included in this study. Twenty-seven patients were treated with Erwinia ASNase (induction therapy 30.000 IU/m2/d i.m. for 10 d, and re-induction therapy 30.000 IU/m2 twice a week for 2 weeks) and 15 were treated with ASNase Medac (induction therapy 1.000 IU/m2/d i.m. for 10 d, and re-induction therapy 5.000 IU/m2 i.m. twice a week for 2 weeks). Blood samples were drawn to determine enzyme activity, l-asparagine, anti-asparaginase antibodies, and coagulation parameters. After i.m. administration, Erwinia ASNase displayed a protracted absorption phase compared to ASNase Medac. The mean bioavailability after i.m. administration was 27% for Erwinia ASNase and 45% for ASNase Medac respectively. Mean trough enzyme activities during induction therapy were Erwinia ASNase 1748 IU/l and ASNase Medac 272 IU/l, and during re-induction therapy Erwinia ASNase 83 IU/l and ASNase Medac 147 IU/l. We conclude that in this setting, therapy with ASNase Medac resulted in sufficient treatment during both phases of therapy, whereas treatment with Erwinia ASNase resulted in unnecessarily intense therapy during the induction phase and insufficient treatment during the re-induction phase. There was no significant difference in the incidence of antibody formation, and therapy with Erwinia ASNase resulted in a more pronounced influence on the coagulation parameters than therapy with ASNase Medac.
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PMID:Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system. 1184 37

Remission induction therapy with vincristine, a corticosteroid, L-asparaginase and an anthracycline has been the mainstay of the initial phase of treatment for childhood acute lymphoblastic leukaemia (ALL) for the past 25 years. The speed and depth of the early response to remission induction therapy has become an important determinant of the intensity of subsequent therapy in many protocols worldwide. Moreover, the detection of significant levels of minimal residual disease at the end of remission induction may have an important bearing on subsequent outcome. Although these clinical observations may reflect, in part, the inherent sensitivity of lymphoblasts to remission induction therapy, the pharmacology of these agents in relation to childhood ALL may also play an important part in early response to therapy. In-vitro studies of human leukaemia cell lines indicate that both the extracellular fluid concentration and duration of exposure to vincristine and anthracyclines are important determinants of cytotoxicity. For L-asparaginase and corticosteroids, the cellular and molecular pharmacological determinants of chemosensitivity have been partially characterized, but further work is needed in this area. The clinical pharmacology of vincristine and L-asparaginase have been well characterized in relation to childhood ALL, and considerable interpatient pharmacokinetic variability exists for these drugs. For corticosteroids and anthracyclines, pharmacology studies are needed in order to fully characterize and understand the factors influencing interpatient pharmacokinetic variability for these agents in relation to childhood ALL. Whereas the relationship between the clinical pharmacology, and potentially important pharmacodynamic effects such as asparagine depletion, has been well characterized for therapy with L-asparaginase, similar studies have yet to be performed for the other drugs that form the mainstay of remission induction therapy for childhood ALL. Therefore, further studies are required to investigate the relative importance of the clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines in the speed and depth of response to remission induction therapy for childhood ALL. Where these have been studied, interindividual differences in the clinical and cellular pharmacology of anticancer agents have been shown to be important determinants of the long-term disease-free survival for children with ALL.
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PMID:Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines. 1190 26

The intensification of post-remission induction therapy has been shown to improve the relapse-free survival for childhood acute lymphoblastic leukaemia (ALL), and is now a standard component of the treatment of childhood acute lymphoblastic leukaemia. For cytosine arabinoside (ara-C), methotrexate, vincristine and corticosteroids, in-vitro studies indicate that the extracellular drug concentration and exposure time are important determinants of cytotoxicity for human leukaemia cell lines. For L-asparaginase, epipodopyllotoxins and cyclophosphamide, there have been few studies of the relationship between cellular pharmacology and cytotoxicity in relation to ALL. The clinical and cellular pharmacology of methotrexate and cytosine arabinoside have been studied in relation to childhood ALL in vivo. For these drugs, there is evidence to suggest that maintenance of plasma concentrations that are biochemically optimal is necessary to maximize anti-leukaemic effects. For cytosine arabinoside in particular, optimal extracellular fluid concentrations are not likely to be achieved or maintained by bolus or short-duration i.v. infusions. A potentially important example of this may be served by the success of antimetabolite-based intrathecal chemotherapy for CNS-directed treatment of childhood ALL. Intrathecal administration of both methotrexate and cytosine arabinoside results in prolonged leukaemic cell exposure to cytotoxic concentrations of the drug. For vincristine, anthracyclines and asparaginase, the actual dose intensity received by children during consolidation therapy may be important, and there is considerable interpatient variation in the pharmacokinetics of cyclophosphamide and teniposide in the therapy of childhood cancers. The importance of this relationship to childhood ALL is not known. The pharmacological and cellular pharmacological studies performed at St Jude Children's Research Hospital (Memphis, TN, USA) have allowed investigation of the relationships between the clinical and cellular pharmacology of methotrexate and prognosis, and have supported the individualization of consolidation therapy with this drug. Cytosine arabinoside has been less well studied in relation to childhood ALL, although evidence exists to suggest that the administration of conventional-dose bolus or infusion schedules may not be optimal in terms of the antileukaemic efficacy of this antimetabolite. For L-asparaginase, ongoing studies may allow the relationship between dose and schedule of administration to be related to pharmacodynamic measures such as asparagine depletion and prognosis. Therefore, through knowledge of clinical and cellular pharmacological properties, it may be possible to optimize the consolidation phase of therapy for childhood ALL, without disrupting the fundamental principles by which the overall treatment is administered. This may be particularly important for children with disease that has inherent or acquired resistance to therapy.
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PMID:Consolidation therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of cytosine arabinoside, epipodophyllotoxins and cyclophosphamide. 1190 27

Signal transduction via protein kinase C (PKC) is closely regulated by its subcellular localization. To map the molecular determinants mediating the C2 domain-dependent translocation of PKCalpha to the plasma membrane, full-length native protein and several point mutants in the Ca(2+)/phosphatidylserine-binding site were tagged with green fluorescent protein and transiently expressed in rat basophilic leukemia cells (RBL-2H3). Substitution of several aspartate residues by asparagine completely abolished Ca(2+)-dependent membrane targeting of PKCalpha. Strikingly, these mutations enabled the mutant proteins to translocate in a diacylglycerol-dependent manner, suggesting that neutralization of charges in the Ca(2+) binding region enables the C1 domain to bind diacylglycerol. In addition, it was demonstrated that the protein residues involved in direct interactions with acidic phospholipids play differential and pivotal roles in the membrane targeting of the enzyme. These findings provide new information on how the C2 domain-dependent membrane targeting of PKCalpha occurs in the presence of physiological stimuli.
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PMID:Role of the Ca2+/phosphatidylserine binding region of the C2 domain in the translocation of protein kinase Calpha to the plasma membrane. 1252 79

L-asparaginases catalyse the formation of the neuroactive amino acid L-aspartate by deamination of asparagine. The major pathophysiological significance of L-asparaginase activity is in its clinical use for the treatment of acute lymphatic leukaemia and neoplasias that require asparagine and obtain it from circulating pools. Here we report the identification and characterization of Gliap, a cytosolic L-asparaginase, which is the founding member of a new group of L-asparaginases in mammalia. Structural modelling suggests that Gliap is an atypical mammalian type-I asparaginase inasmuch as it harbours the active centre of a type-I glycosylasparaginase but, like plant-type asparaginases, lacks their auto-proteolytic site and, in addition, exhibits significant type-II L-asparaginase enzymatic activity. Moreover, in contrast to glycosylasparaginases Gliap is enriched in the cytosolic fraction and not in lysosomes. The protein is particularly abundant in liver, testis and brain. In brain Gliap is exclusively expressed in astrocytes and prominently present in structures reminiscent of glial endfeet. These data suggest that Gliap is involved in astroglial production of the neuroactive amino acid L-aspartate.
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PMID:Gliap--a novel untypical L-asparaginase localized to rat brain astrocytes. 1275 71

Susceptibility to ecotropic murine leukemia viruses (MLV) is restricted to mice and rats at the level of virus binding to the host cell receptor. Asparagine 232, valine 233, tyrosine 235, and glutamic acid 237 in the third extracellular domain (EL3) of the receptor are critical determinants of the host range difference between mice and humans. However, placing these residues in the human homolog confers only partial binding, indicating that other divergent sequences are involved. We sought to determine if the other sequences lie within or outside EL3. Here we report the identification of lysine 234 as another critical residue that influences virus binding and infection, as well as evidence that the unidentified sequences lie outside EL3. Each of the four basic residues in the third extracellular domain were changed to an acidic residue and initially examined in combination with a change at position 235 or position 237. Substitution of lysine 211, 215, or 222 combined with substitution of the critical tyrosine 235 or glutamic acid 237 did not affect virus infection. However, combined substitution of lysine 234, a conserved residue between mice and humans, and tyrosine 235 resulted in a marked decrease in virus infection and binding. A lysine 234 change alone reduced virus binding, contrary to previous observations that at least two of the other four residues must be changed before binding is reduced. Interestingly, there was no decrease in infection when lysine 234 was replaced in combination with glutamic acid 237. This result suggests that residue 234 may act by influencing the local structure of residues 233 to 235, whereas the presence of a glycine at position 236 may prevent this influence from extending to residue 237. With this report, the involvement of all the residues divergent between mice and humans in the third extracellular domain has been ruled out, suggesting that as yet unidentified determinants lie in other extracellular domains.
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PMID:Identification of a critical basic residue on the ecotropic murine leukemia virus receptor. 1285 32

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.
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PMID:Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study. 1463 74

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