UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The now classical major histocompatibility complex (MHC)-restricted receptor for antigen on human T lymphocytes has been identified as a 90 kDa disulphide-linked heterodimer composed of two glycoproteins termed alpha and beta. More recently, another type of T cell receptor for antigen has been described, which seems to mediate killing of target cells without any obvious requirement for MHC recognition. This T cell receptor for antigen is also a heterodimer composed of gamma, delta chains non-covalently associated with the three mon morphic CD3 subunits. Another disulphide-linked dimer capable of triggering T lymphocytes has been defined recently by a monoclonal antibody: the anti-human 9.3 antigen. In order to generate monoclonal or polyclonal reagents against variable and constant regions of the T cell receptor chains and against new epitopes of the 9.3 antigen, we have developed a biochemical method of purification of T lymphocyte disulphide-linked dimers. Our method relies on two biochemical properties of the 9.3 surface molecule and the T cell receptor for antigen. (1) They are disulphide-linked dimers and thus can be separated from the vast majority of the cell surface molecules by two-dimensional (non-reduced versus reduced) sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). (2) T cell receptor chains are less hydrophobic than the 9.3 antigen, and thus can be isolated from it on reverse-phase high-performance liquid chromatography (HPLC) at a lower concentration of acetonitrile. Microsomal preparations from T cell clones and leukaemia lines were prepared by nitrocavitation and lysed in sodium deoxycholate. After concentration, this lysate was electrophoresed on SDS-PAGE in non-reducing conditions. The gel slice corresponding to the molecular weight of the T cell receptor was cut out and run in reducing conditions in the second dimension. The T cell receptor spots were easily located on the gel by autoradiography as the microsomal lysate had been mixed with iodinated glycoproteins. The T cell receptor was eluted from the gel with about 85% yield. At this stage, the T cell receptor preparations also contained the 9.3 antigen, another disulphide-linked dimer. The separation of this antigen from the T cell receptor chains had been achieved on reverse-phase HPLC. This procedure allows the purification and separation of two disulphide-linked dimers which are both involved in T cell activation. The obtention of antibodies against new epitopes of these important molecules would be extremely useful for analysing their role in T cell function and ontogeny.
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PMID:Biochemical purification of various receptor molecules involved in human T lymphocyte activation. Separation of 9.3 antigen from the T cell receptor for antigen. 325 22

10-Acetyl-7,8-dihydroxyxantho[2,3-f]tetralin is obtained by photo-Fries rearrangement of an acylated and double ketal protected tetralin followed by sodium thiocresylate catalyzed rearrangement of the resulting benzoyltetralin. Introduction of the 10-hydroxy function with base, triethyl phosphite, and molecular oxygen affords six products. These include the desired epimeric 10-acetyl-7,8,10-trihydroxyxantho[2,3-f]tetralins in addition to products resulting from novel valence tautomerism and cycloreversion reactions in the oxidation reaction. Glycosidic coupling to the fully functionalized cis-8,10-dihydroxy epimer of the aglycon to protected chlorodaunosamine by a modified Koenigs-Knorr method proceeded satisfactorily. By contrast the epimeric trans-8,10-dihydroxy compound failed to undergo coupling under these conditions. This is attributed to facile competing intramolecular hemiketal formation in the latter case. The new angular glycosides are very resistant to electrochemical reduction and display very low (3-10%) augmentation of hepatic microsomal oxygen consumption relative to doxorubicin. The observed, albeit low, cytotoxicity against leukemia L1210 in cell culture provides an additional example where the presence of the quinone moiety in the parent anthracyclines, which is implicated in the clinical cardiotoxicity, may not be necessary for the expression of anticancer properties.
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PMID:10-Acetyl-10-hydroxyxantho[2,3-f]tetralin 8-glycosides as angular chromophore analogues of anthracyclines: synthesis, redox properties, microsomal oxygen consumption, and antileukemic evaluation. 346 60

We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.
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PMID:Simultaneous administration of multiple model substrates to assess hepatic drug clearance. 358 48

The cytotoxic response of several types of neoplastic cells to analogues of unnatural alkyl phospholipids (e.g., rac-1-hexadecyl-2-methoxy-glycero-3-phosphocholine) has been partially attributed to their accumulation as a result of the low activity of the alkyl cleavage enzyme (a tetrahydropteridine-dependent monooxygenase) in tumor cells. We tested this possibility by comparing the alkyl cleavage enzyme activity in cells that exhibit differences in sensitivity toward the cytotoxic effects of the rac-1-hexadecyl-2-methoxy-glycero-3-phosphocholine. Human promyelocytic leukemia cells (HL-60), a cell line highly sensitive to the cytotoxic alkyl phospholipid analogue, possessed an alkyl cleavage enzyme activity (0.25 pmol/min/microgram protein) similar to that found in three cell types known to be relatively resistant to the cytotoxic activity of the analogue: immature human promyeloblastic leukemia cells (K562) (0.22 pmol/min/microgram protein), human polymorphonuclear neutrophils (0.34 pmol/min/microgram protein), and Madin-Darby canine kidney cells (0.37 pmol/min/microgram protein). Moreover, our results indicate that the cytotoxic rac-1-octadecyl-2-methoxy-glycero-3-phosphocholine analogue is not a substrate for the alkyl cleavage enzyme with an active microsomal preparation of the enzyme from rat liver; cleavage of this analogue was 200-fold less than the rate obtained with 1-octadecylglycerol as substrate. In cultures of either sensitive or resistant type cells, approximately 90% of the added rac-1-[9',10'-3H]octadecyl-2-methoxy-glycero-3-phosphocholine was not metabolized during a 24-h incubation. The amount of radiolabel in fatty acids, a major product of alkyl cleavage activity, was small, and essentially identical amounts were produced in all four cell types [3.1 +/- 0.2% (SD)]. These data indicate that differences in the cellular activities of the alkyl cleavage enzyme are not responsible for the differential cytotoxic responses between normal and specific types of neoplastic cells toward rac-1-octadecyl-2-methoxy-glycero-3-phosphocholine. On the other hand, the cellular uptake of the alkyl phospholipids could be a factor in explaining the cytotoxic response of certain tumor cells, since more radiolabeled 1-octadecyl-2-methoxy-glycero-3-phosphocholine was associated with the susceptible HL-60 cells than with the resistant cell types. Autoradiography revealed that the radiolabeled 2-methoxy analogue accumulates at the periphery of HL-60 leukemia cells, whereas the label was more uniformly distributed in polymorphonuclear neutrophils and K562 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytotoxicity and metabolism of alkyl phospholipid analogues in neoplastic cells. 375 24

When leukotriene (LT) A4 was incubated with subcellular fractions of sonicated rat basophilic leukemia (RBL) cells in the presence of glutathione, the enzyme producing LTC4, designated LTC4 synthetase, was found in the 105,000 X g pellet (microsomes) with a 3-fold enrichment in specific activity over that of the sonicate. The identification of the reaction product as LTC4 was confirmed by its identical retention time on reverse-phase HPLC to that of synthetic LTC4, the incorporation of [3H]glutathione into the product, its reactivity in a radioimmunoassay, and its UV absorption spectrum. In contrast, glutathione S-transferase activity, measured spectrophotometrically with 1-chloro-2,4-dinitrobenzene, was detected predominantly in the 105,000 X g supernatant (89%) and also in the microsomes (7%). The microsomal glutathione S-transferase and LTC4 synthetase were solubilized with 0.4% Triton X-102 and separated by DEAE-Sephacel chromatography; the former appeared in the effluent and the latter in the eluate after the addition of 0.16 M NaCl to the equilibration buffer. Solubilized, microsomal glutathione S-transferase was inhibited by S-hexylglutathione with an IC50 of 36 microM and was stable at 40 degrees C for 5 min, whereas LTC4 synthetase was only slightly inhibited (IC50, 2.3 mM) by S-hexylglutathione and retained no activity after incubation at 40 degrees C for 5 min. The partially purified LTC4 synthetase showed a specific activity of 1.34 +/- 0.51 nmol of LTC4 per 10 min per mg of protein (mean +/- SD, n = 9), representing a 10-fold purification from the sonicate and catalyzed the dose- and time-dependent production of LTC4 from LTA4 and glutathione. The apparent Km values for LTA4 and glutathione were estimated by Lineweaver-Burk plots to be 5-10 microM and 3-6 mM, respectively. These results indicate that the conjugation of LTA4 with glutathione to form LTC4 is catalyzed by a unique microsomal enzyme.
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PMID:Isolation and characterization of leukotriene C4 synthetase of rat basophilic leukemia cells. 386 31

Sudan III treatment of Long-Evans rats results in increased hepatic monooxygenase activity using ethoxycoumarin and aniline as substrates. Monooxygenase activity towards amino-pyrine and nitrosodimethylamine is not affected. Sudan III treatment results in increased microsomal cytochrome P448 and increased amounts of a protein band which comigrates with purified cytochrome P448 during SDS polyacrylamide gel electrophoresis. The proportions of the different dihydrodiols formed during the incubation of 7,12-dimethylbenz[a]anthracene with microsomes vary between untreated and treated animals. Thus, extracts of microsomes from untreated rats were found to contain materials with chromatographic properties identical to those of the 3,4-dihydrodiol and the 5,6-dihydrodiol when examined on two different h.p.l.c. systems. Extracts of microsomes from Sudan III treated animals were found to contain materials with chromatographic properties identical to those of the 5,6-dihydrodiol and the 8,9-dihydrodiol when similarly examined. These findings suggest that the protective effect of Sudan III against DMBA induced leukaemia is mediated by an alteration in monooxygenase activity.
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PMID:Alterations in the metabolism of 7,12-dimethylbenz[a]anthracene and various xenobiotics by rat hepatic microsomes following Sudan III treatment in vivo. 391 57

Mice that had received 10(6) P388 leukemia cells IV 8 days previously exhibited a decrease in the components of the hepatic microsomal mixed function oxidase, with a 58% decrease in cytochrome P-450, and up to a 60% decrease in hepatic microsomal metabolism of biphenyl. Liver weight was increased by 49% due to infiltration of the liver with leukemic cells. Changes in liver drug-metabolizing activity and liver weight were not seen 6 days after administration of P388 leukemia. There was a small increase in serum liver enzyme but no increase in total serum bilirubin in tumor-bearing mice. In vivo total-body plasma clearance of cyclophosphamide, a drug metabolized by hepatic cytochrome P-450, was decreased to 53 ml/min/kg in mice that had received P388 cells 8 days earlier, as against 97.2 ml/min/kg in control mice. Cytochrome P-450-independent metabolism of [14C]5-fluorouracil, measured by means of [14C]CO2 in the breath over 3 h, was decreased to 21% of the dose administered by 8 days after tumor cell administration, compared with 31% of the dose in control mice. P388 leukemia cells growing in the ascitic form in the intraperitoneal cavity of mice did not release an inhibitor of 5-fluorouracil metabolism into the ascitic fluid. Total-body plasma clearance of indocyanine green was decreased to 11 ml/min/kg by 8 days after P388 cell administration, compared with 36 ml/min/kg in control mice. The decrease in indocyanine green clearance might reflect a decrease in hepatic blood flow in the tumor-bearing mice. A possible explanation for the decrease in hepatic drug metabolism caused by P388 leukemia is that the hepatocytes are deprived of oxygen and nutrients by the tumor in the liver, coupled with or caused by a physical obstruction of hepatic blood flow.
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PMID:Effects of advanced leukemia on hepatic drug-metabolizing activity in the mouse. 394 Feb 19

The chemical synthesis of 9-hydroxyolivacine and 7-hydroxyolivacine based on a biomimetic approach is described. These two hydroxylated derivatives have been found as main in vitro metabolites of olivacine after incubation with rat hepatic microsomes. The pretreatment of animals with benzo[a]pyrene caused a large increase in both microsomal hydroxylations, whereas the pretreatment with phenobarbital caused a weak increase, with a preservation of 9-hydroxylation/7-hydroxylation ratio greater than 1 in both cases. The two hydroxyolivacines have been also found as principal in vivo metabolites of olivacine in rat bile as glucuronide and sulfate conjugates. The pretreatment of animals with benzo[a]pyrene reverses the 9-hydroxyolivacine/7-hydroxyolivacine ratio excretion in bile to a value that is less than 1. In both in vitro and in vivo experiments, the free metabolites were identified by HPLC and UV-visible, MS, and 1H NMR spectra. Hydroxylation at position 9 increases the in vitro cytotoxicity against leukemia L1210 cells (ID50 = 0.06 microM compared to 2.03 microM for olivacine) and an opposite effect is observed for hydroxylation at position 7 (ID50 = 12.8 microM). On the other hand, hydroxylation at position 9 has no effect on the in vivo antitumor activity against L1210. This might be related to the oxidative and conjugative metabolic pathways that play an important role in antitumor activity and deactivation of olivacine and its hydroxy metabolites.
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PMID:Synthesis and cytotoxic activity of hydroxylated derivatives of olivacine in relation with their biotransformation. 400 91

The virus proteins, reverse transcriptase (RT) and p30, were found to increase with time in the subcellular fractions of lymphocytic tissue from either the thymus or spleen of AKR mice with spontaneous lymphocytic leukaemia. Significant levels of RT activity were first detected in the microsomal fractions of the two tissues at 15 and 20 weeks old, respectively. Although low amounts of p30 could be found in both tissues within the first week of life, the overall increase in the amount of p30 within each tissue followed much the same course as that shown by RT. In addition, a protein complex consisting of p30 and RT was first found in thymus and spleen lymphocytes of 15 and 20 week-old animals, respectively. The complex increased in amount in both organs as the animals aged, reaching a maximum level in 30 week-old mice. Repeated attempts to detect other virus proteins such as gp70 in association with the complex by immunological means were unsuccessful. The complex could not be found in lymphocytic tissue taken from younger animals or in 'non-target' organs, such as liver or kidney, of animals with leukaemia. In animals treated with antiviral IgG, which delayed the development of spontaneous leukaemia, the complex did not appear until much later in life (45 weeks) and then in considerably smaller amounts.
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PMID:Existence of a reverse transcriptase-p30 complex in AKR mice with a high incidence of spontaneous lymphocytic leukaemia. 616 45

An RNA-directed DNA polymerase was purified from mouse spleen infected with leukaemia virus activated during N-methyl-N-nitroso urea- (MNU-) induced leukaemogenesis. The enzyme was isolated from the microsomal fraction and purified by successive chromatography of Sephadex G-200 and phosphocellulose. Estimation of molecular weight from the sedimentation rate of the purified enzyme in a sucrose gradient gave a value of 70,000. The enzyme had a pH optimum of 7.4, a KC1 optimum of 50 mmol/l, an Mn2+ optimum of 0.2 mmol/l, and a temperature optimum of 25 degrees C, when (rA)n . (dT) 10 was used as the template-primer. It preferred (rA)n . (dT)10 as the template-primer and transcribed (rC)n . (dG) 12 and (OMeC)n . (dG)12. A comparison of the properties of this DNA polymerase with the enzyme purified from murine type C retroviruses showed that the MNU-activated virus enzyme was both biochemically and biophysically indistinguishable from murine leukaemia virus DNA polymerases.
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PMID:Characterization of an RNA-directed DNA polymerase from mouse spleen infected with leukaemia virus activated during N-methyl-N-nitroso urea-induced leukaemogenesis. 617 78

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