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)

Lovastatin blocks the biosynthesis of the isoprenoid precursor, mevalonate. When Friend murine erythroleukemia (MEL) cells are cultured in medium containing lovastatin, the precursor of murine leukemia virus envelope glycoprotein (gPr90env) fails to undergo proteolytic processing, which normally occurs in the Golgi complex. Consequently, newly synthesized envelope proteins are not incorporated into viral particles that are shed into the culture medium. gPr90env appears to be localized in a pre-Golgi membrane compartment, based on its enrichment in subcellular fractions containing NADPH-cytochrome c reductase activity and the sensitivity of its carbohydrate chains to digestion with endoglycosidase H. Arrest of gPr90env processing occurs at concentrations of lovastatin that are not cytostatic, and the effect of the inhibitor is prevented by addition of mevalonate to the medium. The low molecular mass GTP-binding proteins, rab1p and rab6p, which are believed to function in early steps of the exocytic pathway, are normally modified posttranslationally by geranylgeranyl isoprenoids. However, in MEL cells treated with 1 microM lovastatin, nonisoprenylated forms of these proteins accumulate in the cytosol prior to arrest of gPr90env processing. These observations suggest that lovastatin may prevent viral envelope precursors from reaching the Golgi compartment by blocking the isoprenylation of rab proteins required for ER to Golgi transport.
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PMID:Isoprenoid requirement for intracellular transport and processing of murine leukemia virus envelope protein. 142 16

A cyclophosphamide resistant subline (BNML/CPR) was developed in vivo in the BN rat acute myelocytic leukaemia (BNML) model. Full resistance was achieved after in vivo exposure of leukaemic animals to cyclophosphamide with, in total, 15 intraperitoneal injections of 100 mg/kg. The CPR line was cross-resistant to ifosfamide, but less so to mafosfamide. Continuous transplantation of the BNML/CPR line without a cyclophosphamide selection pressure resulted in the emergence of a subline (BNML/CPR greater than S) whose sensitivity to cyclophosphamide was similar to that of the parent BNML/S line. Both in the BNML parent line and in the BNML/CPR greater than S line, a 2p+ marker chromosome was present, whereas a 2p+q+ marker chromosome was characteristic for the BNML/CPR line. The mechanism of cyclophosphamide resistance can now be investigated in the BNML model at the DNA, at the mRNA and at the protein level.
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PMID:Development and characterisation of a cyclophosphamide resistant variant of the BNML rat model for acute myelocytic leukaemia. 182 81

Merocyanine 540 (MC 540) is a photosensitizing dye that is used clinically for the purging of autologous bone marrow grafts and preclinically for the inactivation of enveloped viruses in blood products. Its mechanism of action is not yet well understood. This paper investigates the sites of MC 540-mediated photodamages in L1210 leukemia cells by examining the effects of MC 540-sensitized photoirradiation on several soluble and membrane-bound marker enzymes. When exposed to MC 540 and white light under a standard set of conditions, the activities of Na+/K(+)-ATPase, Mg2(+)-ATPase, and 5'-nucleotidase (three plasma membrane-bound enzymes) were reduced by 54, 49, and 55%, respectively. None of the intracellular enzymes included in this survey was affected by MC 540-sensitized photoirradiation as long as the plasma membrane remained intact. The two soluble enzymes, lactate dehydrogenase and malate dehydrogenase, remained refractory to MC 540-sensitized photoirradiation even after the plasma membrane had been disrupted. By contrast, the activities of the membrane-bound enzymes, NADPH-cytochrome c reductase and succinate dehydrogenase, were reduced in cell lysates by 55 and 81%, respectively. Purified NADPH-cytochrome c reductase was about 3 times less sensitive than the microsomal enzyme, suggesting that the membrane environment facilitated photoinactivation. The MC 540-sensitized photoinactivation of enzymes was accelerated in the presence of deuterium oxide and inhibited if oxygen in the medium was displaced by nitrogen or azide was added to the medium. Taken together, these data support the view that the plasma membrane is a major target of MC 540-mediated photodamages, that the inactivation of membrane-bound enzymes is an oxidative process, and that at least some photodynamic damages are mediated by type II chemistry.
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PMID:Merocyanine 540-sensitized photoinactivation of soluble and membrane-bound enzymes in L1210 leukemia cells. 217 31

In mice, there is a correlation between genetically regulated levels of inducible aryl hydrocarbon hydroxylase (AHH) activity and the risk of polycyclic hydrocarbon-induced leukemia or solid tumors. Recent clinical studies suggest a relationship between high AHH activity and lung cancer associated with cigarette smoking (Kouri, R.E., McKinney, C.E., Slomiany, D.J., Snodgrass, D.R., Wray, N.P., and McLemore, T.L. Cancer Res. 42: 5030-5037, 1982). To determine whether there is a similar genetic relationship in humans between inducible AHH and the occurrence of pediatric cancers, we examined AHH activity in mitogen-stimulated benzo(a)anthracene-treated lymphocyte cultures from primary relatives of children with leukemia or solid tumors. Control families (parents and siblings with no history of cancer) comprised friends or neighbors of the proband families. By comparing variance among family members with variance among nonrelated individuals, we conclude that a small, but real, genetic component is detectable. Adjusting for age, smoking history, and the length of time during which the lymphocytes had been cryopreserved, however, we find no difference among 77 leukemia, 71 solid tumor, and 100 control family members with regard to median units (+/- median S.E.) of maximally induced AHH activity per unit of reduced nicotinamide adenine dinucleotide-cytochrome c reductase activity: 0.31 +/- 0.03; 0.28 +/- 0.03; and 0.28 +/- 0.03, respectively. Thus, benzo(a)anthracene-induced AHH activity in cultured mitogen-activated lymphocytes in our study population does not appear to be associated with the risk of occurrence of childhood leukemia or solid tumors.
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PMID:Aryl hydrocarbon hydroxylase inducibility among primary relatives of children with leukemia or solid tumors. 669 48

The development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance. The role of the CP-detoxifying enzyme aldehyde dehydrogenase (ALDH) in the molecular mechanism of CP resistance in this subline of the BNML has been investigated. Compared to the parent BNML cell line, the BNML/CPR cell line displayed an approximately 6-fold higher level of ALDH enzyme activity. Pretreatment of leukaemic rats with the ALDH inhibitor disulfiram resulted in a restoration of CP sensitivity of animals carrying the BNML/CPR cells. Furthermore, in vitro incubation of BNML/CPR cells with disulfiram prior to incubation with the activated CP derivative mafosfamide resulted in an extra 2-3 log cell kill as indicated by the survival time of rats which were injected with disulfiram pretreated BNML/CPR cells compared to non-pretreated BNML/CPR cells. Data on the glutathione S-transferases (GSTs) isozyme profiles of cytoplasmic liver and spleen extracts of BNML- and BNML/CPR-carrying leukaemic rats indicated that the total GST enzyme amount was lower in BNML/CPR cells than in parent BNML cells. Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro.
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PMID:Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo. 785 14

Regarding problems in emergency and urgent immunoserologic tests, I mainly focused on infectious diseases and CPR and discussed the correspondence of dangerous needle stick injuries, and the significance of emergency CRP measurement in various body fluids using highly sensitive determination methods. The actual conditions and correspondence of infections due to dangerous needle stick injuries (accidental pricking with used needles) such as hepatitis, syphilis, acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia (ATL), herpes simplex, falciparum malaria, tuberculosis, Rocky mountain spotted fever, and human colonic adenocarcinoma are discussed. With regard to emergency CRP measurement, application of highly sensitive determination methods and the significance of CRP measurement of various body fluids (healthy adult blood, cord blood, cerebrospinal fluid, urine and puncture fluid) are described. The reference values for CRP concentrations in various body fluids were established at 15 to 3,063 ng/ml for serum (male; 26 to 3.992 ng/ml, female; 11 to 1,672 ng/ml), 9 to 73 ng/ml for cord blood, 2 to 10 ng/ml for cerebrospinal fluid and less than 2 ng/ml for urine.
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PMID:[Future prospects of emergency laboratory tests--problems of immunoserologic tests]. 893 87

A selected suite of cytochemical parameters in Mytilus edulis are altered in response to field and laboratory exposure to chemical contaminants. These biomarkers include lysosomal stability, nicotinamide adenine dinucleotide phosphate (NADPH)-ferrihemoprotein reductase activity, liposfuscin deposition, and accumulation of lysosomal and cytoplasmic unsaturated neutral lipid. Normal variations in physiological processes (influenced by exogenous seasonal changes in temperature, salinity, food availability, etc.) may alter the sensitivity of these biomarkers to contaminant exposure. To address this issue, M. edulis (complex) were sampled monthly from a reference nonurban site (Coupeville, Penn Cove) and a polluted urban site (Seacrest, Elliott Bay) in Puget Sound, WA, for a period of 15 months. Physiological measurements including total length, total weight, somatic and mantle weights (an indication of gonadal development and reproductive status), condition index, and the presence or absence of hemic neoplasia (HN, or leukemia) were recorded. Significant differences in lysosomal stability, lysosomal and cytoplasmic unsaturated neutral lipids, lipofuscin deposition, and NADPH-ferrihemoprotein reductase activity in cells of the digestive gland or digestive tubules were generally found in mussels taken throughout the year from Seacrest compared to mussels sampled from Coupeville, consistent with exposure to chemical contaminants. No seasonally influenced suppression of the entire suite of parameters as measures of contaminant exposure was evident. Therefore these biomarkers can be used to evaluate contaminant exposure in mussels throughout the entire year.
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PMID:Assessment of seasonal variability of cytochemical responses to contaminant exposure in the blue mussel Mytilus edulis (complex). 1243 18

Many chromones, especially those having 2-substituents, manifest a remarkable variety of biological activities, such as the important cytotoxicity against human leukaemia cells, antiallergic, anticancer activities; unfortunately chromones normally disturb mitochondrial bioenergetics. A new 2-styrylchromone has been synthesized by the Baker-Venkataraman method and a classical approach has been used to assess the effects of 2-styrylchromone (3'-allyl-4',5,7-trimethoxy-2-styrylchromone) on rat liver mitochondrial bioenergetic. Mitochondrial respiratory rate and transmembrane potential were measured polarographically using a Clark oxygen electrode and with a selective electrode, respectively. All the disturbance induced by 2-styrylchromone on the enzymatic activities (succinate dehydrogenase, succinate cytochrome c reductase, and cytochrome c oxidase) and in the mitochondrial osmotic volume were determined spectrophotometrically. State 4, state 3, and uncoupled (presence of carbonylcyanide p-trifluoromethoxyphenylhydrazone) respiration rates were decreased by 2-styrylchromone in a concentration-dependent manner. Depression of respiratory activity promoted by 2-styrylchromone is essentially mediated through partial inhibition of succinate cytochrome c reductase. Phosphorylation capacity was strongly depressed as a result of an inhibition on the enzymatic complex (F(0)F(1)-ATPase) and also because of a deleterious effect on the integrity of the mitochondrial membrane, which uncoupled the respiration-generated proton gradient with the proton-driven phosphorylation. The structural integrity of the outside membrane is severely affected since cytochrome c can be released. 2-Styrylchromone uncouples oxidative phosphorylation by an inhibitory action on the redox chain and ATP synthase activity. Additionally, it can release cytochrome c. Cell death can probably result due to the induction of procaspase-9 and other procaspases and by a strong decrease of the available ATP.
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PMID:Interactions of a new 2-styrylchromone with mitochondrial oxidative phosphorylation. 1243 63

Because of the limited availability of human tissues, leukemia cell lines are often utilized as the models for human leukocytes. In this study, we investigated the NADPH-dependent reductases and polyol pathway in commonly utilized human leukemia cell lines. The relative amounts of aldose and aldehyde reductases were estimated by separating two enzymes with chromatofocusing. The flux of glucose through the polyol pathway was examined by 19F-NMR using 3-fluoro-3-deoxy-D-glucose (3FG) as substrate. Sugar alcohol analysis was conducted by gas chromatography. In myelocytic leukemia cells, the major reductase was aldehyde reductase, and levels of aldose reductase were extremely low. Although lymphocytic cells also contained both aldose and aldehyde reductases, the levels of aldose reductase appeared to be higher in lymphocytic cells than myeolcytic cells. In two lymphocytic cells MOLT-4 and SKW6.4, aldose reductase is clearly dominant. When incubated in medium containing D-galactose, all cell lines quickly accumulated galactitol. There was correlation between galactitol levels and aldose reductase levels. The aldose reductase inhibitor FK 366 significantly reduced the formation of galactitol. 19F-NMR of the cells cultured with 3FG as substrate demonstrated the formation of 3-fluoro-3-dexoy-sorbitol in all the cell lines examined in this study. The relative amounts of sorbitol and fructose varied significantly among the cells. The data confirm that the polyol pathway is present in both myelocytic and lymphocytic leukemia cell lines. However, there is a large variation among the cell lines in the levels of enzymes and flux of glucose through the polyol pathway.
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PMID:NADPH-dependent reductases and polyol formation in human leukemia cell lines. 1260 23

Experimental hyperoxia represents a suitable in vitro model to study some pathogenic mechanisms related to oxidative stress. Moreover, it allows the investigation of the molecular pathophysiology underlying oxygen therapy and toxicity. In this study, a modified experimental set up was adopted to accomplish a model of moderate hyperoxia (50% O(2), 96 h culture) to induce oxidative stress in the human leukemia cell line, U-937. Spectrophotometric measurements of mitochondrial respiratory enzyme activities, NMR spectroscopy of culture media, determination of antioxidant enzyme activities, and cell proliferation and differentiation assays were performed. The data showed that moderate hyperoxia in this myeloid cell line causes: i) intriguing alterations in the mitochondrial activities at the levels of succinate dehydrogenase and succinate-cytochrome c reductase; ii) induction of metabolic compensatory adaptations, with significant shift to glycolysis; iii) induction of different antioxidant enzyme activities; iv) significant cell growth inhibition and v) no significant apoptosis. This work will permit better characterization the mitochondrial damage induced by hyperoxia. In particular, the data showed a large increase in the succinate cytochrome c reductase activity, which could be a fundamental pathogenic mechanism at the basis of oxygen toxicity.
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PMID:Mitochondrial damage and metabolic compensatory mechanisms induced by hyperoxia in the U-937 cell line. 1546 33


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