RESUMEN
The objective was to study the independent relationships of body mass index and endogenous estradiol to cortical bone mineral density and the rate of cortical bone loss at the radius in healthy early postmenopausal women. Fifty-one healthy early postmenopausal women (aged 58-66 years) participated. The women were a subset of a population participating in a 10-year longitudinal study to elucidate the influence of dietary calcium on the rate of cortical bone loss. Cortical bone mineral density at the radius, body weight and body height were measured annually (1979-89). Concentrations of sex steroids were measured in serum samples collected during the last year of follow-up (1989). Endogenous estradiol levels, although significantly positively correlated with body mass index, were not independently related to bone mass indices of the radius. Body mass index, on the other hand, was found to be positively related to cortical bone mineral density and negatively to the rate of bone loss, even after adjustments had been made for confounding factors. Our results suggest that the level of total estradiol is not an important determinant of cortical bone mass indices in healthy early postmenopausal women. Other factors of overweight such as mechanical loading may be important.
Asunto(s)
Peso Corporal , Densidad Ósea , Estradiol/sangre , Osteoporosis Posmenopáusica/patología , Anciano , Índice de Masa Corporal , Calcio de la Dieta/farmacología , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/sangreRESUMEN
Methotrexate (MTX) and 6-mercaptopurine (6MP) are common drugs in the oral maintenance therapy of acute lymphoblastic leukemia (ALL). On the basis of their biochemical effects on cell metabolism, a sequence-dependent synergism might be anticipated. In order to investigate this hypothesis, MOLT-4 human malignant T-lymphoblasts were incubated with various concentrations of MTX. The time at which maximal increase of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) levels was found correlated with the concentrations of MTX used. Determination of aminoimidazolecarboxamide ribonucleoside monophosphate (AICAR) levels and labeled glycine incorporation into purine metabolites revealed an incomplete inhibition of purine de novo synthesis after incubation with 0.02 microM MTX, and a complete inhibition with 0.2 microM MTX. After prolonged periods of incubation, glutamine exhaustion of the medium caused inhibition of purine de novo synthesis in MTX-untreated cells, with a concomitant increase of PRPP levels. Addition of glutamine to the medium prevented this phenomenon. The increased availability of PRPP after pretreatment with MTX can be used for enhanced intracellular incorporation of hypoxanthine and 6MP in their respective nucleotides. The time- and dose-dependent effects of MTX on PRPP levels correlated with the enhanced incorporation of hypoxanthine and 6MP. The data presented in this study demonstrate that a synergistic action of the combination of MTX and 6MP can be anticipated in malignant lymphoblasts with an active purine de novo synthesis depending on the concentration of MTX and on the time and sequence of administration of both drugs.
Asunto(s)
Leucemia Linfoide/tratamiento farmacológico , Mercaptopurina/uso terapéutico , Metotrexato/uso terapéutico , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/análisis , Línea Celular , Sinergismo Farmacológico , Glutamina/metabolismo , Glicina/metabolismo , Humanos , Hipoxantina , Hipoxantinas/metabolismo , Fosforribosil Pirofosfato/metabolismo , Purinas/metabolismo , Ribonucleótidos/análisis , Linfocitos TAsunto(s)
Buserelina/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Fosfatasa Ácida/sangre , Anciano , Buserelina/administración & dosificación , Preparaciones de Acción Retardada , Evaluación de Medicamentos , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Testosterona/sangreAsunto(s)
Mercaptopurina/metabolismo , Metotrexato/farmacología , Pentosafosfatos/metabolismo , Fosforribosil Pirofosfato/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Línea Celular , Humanos , Purinas/biosíntesis , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoAsunto(s)
Adenosina/fisiología , Receptores Purinérgicos/fisiología , Linfocitos T/fisiología , Timo/fisiología , 2-Cloroadenosina , 4-(3-Butoxi-4-metoxibencil)-2-imidazolidinona/farmacología , Adenosina/análogos & derivados , Adenosina/metabolismo , Adulto , Preescolar , Coformicina/farmacología , AMP Cíclico/metabolismo , Humanos , Técnicas In VitroAsunto(s)
Adenosina/toxicidad , ADN/biosíntesis , Desoxiadenosinas/toxicidad , Linfocitos/efectos de los fármacos , Inhibidores de la Adenosina Desaminasa , Línea Celular , Células Cultivadas , Coformicina/análogos & derivados , Coformicina/farmacología , Humanos , Activación de Linfocitos/efectos de los fármacos , Linfocitos/citología , Mitógenos , Pentostatina , Timidina/metabolismoRESUMEN
A survey is given of our present investigations of the pharmacokinetics of 6MP and the effects of the combination of MTX and 6MP on purine and pyrimidine metabolism. Both drugs are used in the oral maintenance therapy of ALL in children. The very low serum-concentrations after oral administration of 6MP and the short serum-half-life-times after intravenous administration point to more efficacy after prolonged intravenous infusion. The penetration of 6MP in the cerebrospinal fluid after intravenous administration could account for (prophylactic) treatment of the CNS in ALL. Pretreatment of leukemic lymphoblasts with MTX results in an increase of intracellular PRPP due to inhibition of purine de novo synthesis. This can be used for an increased incorporation and conversion of 6MP. Thus, increased incorporation and conversion of 6MP can be obtained when 6MP is added to MTX-pretreated leukemic lymphoblasts at that point of time where MTX causes maximal PRPP accumulation. This will result in increased incorporation of 6MP into nucleic acids and thus in enhanced cytotoxicity. Pharmacokinetic and metabolic investigations of 6MP and MTX could lead to a more rational and more effective use of both agents in patients with ALL.
Asunto(s)
Mercaptopurina/metabolismo , Metotrexato/metabolismo , Animales , Niño , Perros , Semivida , Humanos , Infusiones Parenterales , Leucemia Linfoide/tratamiento farmacológico , Linfocitos/metabolismo , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Purinas/sangre , Pirimidinas/sangreAsunto(s)
Adenina/análogos & derivados , Adenosina/farmacología , Inmunosupresores/farmacología , Activación de Linfocitos/efectos de los fármacos , Mitógenos , Adenina/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Replicación del ADN/efectos de los fármacos , Humanos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaAsunto(s)
Leucemia Linfoide/enzimología , Purinas/metabolismo , 5'-Nucleotidasa , Adenosina Desaminasa/sangre , Adolescente , Niño , Preescolar , Humanos , Lactante , Leucemia Linfoide/inmunología , Nucleotidasas/sangre , Purina-Nucleósido Fosforilasa/sangre , Linfocitos T/enzimología , Linfocitos T/inmunologíaAsunto(s)
Purinas/metabolismo , Linfocitos T/fisiología , 5'-Nucleotidasa , Adenosina Desaminasa/metabolismo , Adenilato Quinasa/metabolismo , Diferenciación Celular , Preescolar , Desoxicitidina Quinasa/metabolismo , Humanos , Lactante , Activación de Linfocitos , Nucleotidasas/metabolismo , Purina-Nucleósido Fosforilasa/metabolismo , Linfocitos T/inmunología , Timo/fisiologíaRESUMEN
The combination of centrifugal elutriation as an efficient and reproducible method to separate thymocytes by size, micromethods to assess purine interconversion enzymes, and assessment of purine (deoxy)nucleoside inhibition of mitogen responses enabled us to study purine metabolism at the intrathymic level. Out of six fractions, four (nos. 3-6), containing medium- and large-sized lymphocytes, showed a proliferative response after stimulation with phytohaemagglutinin (PHA). In fractions 1-6 the number of cells with an immature immunological phenotype gradually decreased, and cells with the phenotype of mature cells gradually increased. The enzyme activity ratio of adenosine deaminase to purine nucleoside phosphorylase gradually decreased from 21 in fraction 1 to 7 in the last fraction (blood T-cell value, 0.7). We conclude that this enzyme activity ratio is a useful marker for intrathymic T-cell maturation stages. In PHA-responsive cell fractions (3-6), the sensitivity to inhibition of the PHA response by (deoxy)adenosine and deoxyguanosine was inversely related to the enzyme activity ratio of ecto-5'-nucleotidase to deoxycytidine kinase. These findings are compatible with the hypothesis that intracellular concentrations of phosphorylated (deoxy)nucleosides are related to this inhibition. We conclude that the differences in purine metabolism among the various (mitogen-responsive) human thymocyte fractions are related to lymphoid cell function. Since the number of cells contributing to the enzyme activities and the number of cells contributing to the proliferative response (about 15% of unseparated cells) differ considerably, it is not possible to evaluate enzyme activities in unseparated thymocytes in terms of relationships between purine metabolism and lymphocyte function.
Asunto(s)
Linfocitos/metabolismo , Purinas/metabolismo , Timo/citología , Adenosina Desaminasa/metabolismo , Separación Celular/métodos , Preescolar , Desoxicitidina Quinasa/metabolismo , Inhibidores Enzimáticos , Humanos , Lactante , Activación de Linfocitos/efectos de los fármacos , Linfocitos/enzimología , Nucleótidos/metabolismo , Purina-Nucleósido Fosforilasa/metabolismo , Linfocitos T/metabolismoRESUMEN
A number of inborn errors of purine metabolism have been associated with immunodeficiency diseases. From studies to the possible mechanism(s) leading to the defects in the immune system, it appeared that the accumulation of deoxyATP and deoxyGTP and the subsequent inhibition of ribonucleotide reductase played an important role. The inhibition of methylation pathways through the accumulation of s-adenosylmethionine seems to be a second valid concept. The amount to which certain subtypes of lymphoid cells were affected by the enzyme deficiencies was strongly related to the enzymatic make-up of the cells. Lymphoid cells from different maturation stages could be affected in a specific way, depending on the different enzyme activities of these cells. Studies on human lymphoblastic leukemias showed that, related to the immunological subtype, the different leukemias could be characterized by a different enzymatic make-up. In this paper we discuss the possibilities for a specific enzyme directed chemotherapy, directed against specific subtypes of human lymphoblastic leukemias. Experimental evidence indicates that for example the adenosine deaminase inhibitor 2'deoxycoformycin can be used as a specific drug against acute lymphoblastic leukemia with the T cell phenotype.
Asunto(s)
Hematopoyesis , Síndromes de Inmunodeficiencia/metabolismo , Leucemia Linfoide/metabolismo , Linfocitos/metabolismo , Purinas/metabolismo , Adenosina/farmacología , Adenosina Desaminasa/deficiencia , Diferenciación Celular , AMP Cíclico/metabolismo , Humanos , Leucemia Linfoide/tratamiento farmacológico , Fosforribosil Pirofosfato/metabolismo , Purina-Nucleósido Fosforilasa/deficiencia , Pirimidinas/metabolismo , Ribonucleótido Reductasas/metabolismoRESUMEN
Adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), 5'nucleotidase (5'NT), ecto-5'NT, hypoxanthine-guanine phosphoribosyltransferase(HGPRT), adenine phosphoribosyltransferase(APRT), adenosine kinase(AK), AMP deaminase (AMPD) and adenylate kinase(AdKin) activities were assayed in leukemic cells from bone marrow and/or peripheral blood of 43 newly diagnosed children with acute lymphoblastic leukemia(ALL). These enzyme activities have been investigated in relation to some immunological markers. ADA activity was higher in E-rosette positive leukemia(E+ ALL), while HGPRT, APRT, PNP, 5'NT, ecto-5'NT and AdKin activities were found to be lower in E+ ALL as compared to E- ALL. In common ALL (cALL) antigen positive leukemia, mean ADA activity was significantly lower as compared to cALL- leukemia, whereas PNP, 5'NT, ecto-5'NT and AdKin activities were significantly higher. cALL cells with cytoplasmic immunoglobulin M(IgM) heavy chains were found to have mean 5'NT activities twice as high as cALL cells lacking cytoplasmic IgM heavy chains. In two patients who had surface immunoglobulins on their cell membranes, low 5'NT activities were found. When measuring enzyme activities after 2-4 days of prednisone monotherapy, only mean ADA and HGPRT activities decreased in non-B, non-T ALL. These decreases were not significant in T-ALL patients. Mean enzyme activities in the leukemic cells of five patients with relapse were comparable to those in newly diagnosed patients, except for 5'NT, which was found to be within the activity range of control peripheral blood lymphocytes. It is concluded that ADA and AdKin activities are suitable as markers for E+ ALL and cALL+ leukemias respectively. 5'NT might help to distinguish between cALL cells having and lacking pre-B characteristics. Since 5'NT activity may also be decreased in B-ALL, it is not suitable as a T-ALL marker. Enzymes of purine metabolism in leukemic relapse need further investigation.
Asunto(s)
Leucemia Linfoide/enzimología , Purinas/metabolismo , 5'-Nucleotidasa , AMP Desaminasa/metabolismo , Adenina Fosforribosiltransferasa/metabolismo , Adenosina Desaminasa/metabolismo , Adenosina Quinasa/metabolismo , Adenilato Quinasa/metabolismo , Adolescente , Médula Ósea/enzimología , Niño , Preescolar , Humanos , Hipoxantina Fosforribosiltransferasa/metabolismo , Lactante , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/tratamiento farmacológico , Leucemia Linfoide/inmunología , Nucleotidasas/metabolismo , Purina-Nucleósido Fosforilasa/metabolismoRESUMEN
Adenosine deaminase (ADA), 5'nucleotidase (5'NT), ecto-5'NT, purine nucleoside phosphorylase (PNP), hypoxanthine-guanine phosphoribosyltransferase (HGPRT), adenine phosphoribosyltransferase (APRT), adenosine kinase (AK), AMP-deaminase (AMPD) and adenylate kinase (AdKin) activities were assayed in peripheral blood lymphoid cells from 20 patients with B-cell type chronic lymphocytic leukemia (CLL). Significantly decreased mean activities of ADA, 5'NT, ecto-5'NT, PNP and AMPD were observed when comparing B-CLL lymphoid cells with control peripheral blood lymphocytes (PBL). AK and AdKin activities however, were found to be higher in B-CLL. Relatively wide ranges of ADA and 5'NT activity were observed. In patients with paraproteinaemia, 5'NT activity was found to be relatively high and in the range of the activities in normal PBL. ADA activity seemed to be slightly higher in patients without paraproteinaemia. No correlation could be found between the enzyme activities and the number of cells rosetting with sheep erythrocytes or bearing surface immunoglobulin (sIg). A relationship was suggested between 5'NT activity and Ig production.