RESUMO
We studied twin brothers who met all diagnostic criteria for the Kearns-Sayre syndrome (KSS). The twins reinforce the view that KSS is a specific syndrome. They raise the possibility that the condition is inherited as a lethal dominant trait, a mode of inheritance that explains the observed paucity of familial cases. However, these cases do not exclude the possibility of an acquired cause, such as persistent viral infection of the brain.
Assuntos
Doenças em Gêmeos , Síndrome de Kearns-Sayre/genética , Oftalmoplegia/genética , Adulto , Fatores Etários , Doenças Genéticas Inatas/genética , Humanos , Síndrome de Kearns-Sayre/etiologia , Masculino , Gêmeos MonozigóticosRESUMO
A mouse L1210 leukemia cell line was made 25-fold resistant to methotrexate (MTX) and had altered methionine transport and metabolism. L1210 cells resistant to methotrexate also had a 50-fold decrease in the exogenous methionine requirement for optimal cell growth compared to the parent cells. This change in methionine requirement was associated with differences in methionine metabolism between MTX-sensitive and MTX-resistant cell lines. Analysis of amino acid transport systems revealed different Kt and Vmax properties of methionine and nonmetbolizable amino acid analogues. There was a greater than twofold decrease in the initial sodium-dependent uptake of methionine in the resistant cells. Amino acid competition experiments revealed altered substrate specificities in the resistant cells. The cellular alterations occurring upon resistance may result from methotrexate-membrane interactions, and have been previously observed in cisplatinum-resistant cells. Thus modulation of methionine metabolism may provide the biochemical basis for MTX and cisplatinum collateral resistance.
Assuntos
Leucemia L1210/metabolismo , Metionina/fisiologia , Metotrexato/farmacologia , Animais , Transporte Biológico Ativo , Linhagem Celular , Cisplatino/farmacologia , Resistência a Medicamentos , Antagonistas do Ácido Fólico , Cinética , Leucemia L1210/patologia , Metionina/metabolismo , Metotrexato/metabolismo , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Sódio/farmacologiaRESUMO
Methionine-auxotrophic L1210 cells were used to study the effect of methotrexate (MTX) on methionine uptake and metabolism. MTX was shown to inhibit amino acid transport systems and cause a decrease of methionine uptake into L1210 cells. Conversely, a nonmetabolizable amino acid analogue reduced MTX uptake into L1210 cells. MTX also blocked the transfer of the beta carbon from serine into methionine. Therefore, methionine deprivation may be an additional mechanism of action for MTX in methionine-auxotrophic tumor cells.
Assuntos
Leucemia L1210/metabolismo , Metionina/metabolismo , Metotrexato/farmacologia , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Linhagem Celular , Depressão Química , Leucemia L1210/patologia , Metionina/biossíntese , Metotrexato/metabolismo , Camundongos , Serina/metabolismoRESUMO
Mitogen stimulation of human lymphocytes was used to study the expression of several amino acid transport systems in response to cell growth. Resting lymphocytes possess detectable neutral amino acid transport systems which can be activated by the mitogen, phytohemagglutinin (PHA). Sodium-independent transport of 2-aminobicyclo (2,2,1) heptane 2-carboxylic acid was similar in resting and stimulated lymphocytes. However, sodium-dependent uptake of methyl aminoisobutyric acid and alpha-aminoisobutyric acid increased threefold to eightfold with stimulation by PHA. Methionine uptake was primarily sodium-independent in resting lymphocytes, whereas methionine uptake increased fourfold to eightfold in stimulated cells; most of this increase was attributable to sodium-dependent transport. Uptake of methotrexate (MTX) was minimal in resting lymphocytes but was maximal 72 hrs after stimulation with PHA; this increase in MTX uptake was accompanied by inhibition of sodium-dependent methionine transport. These results suggest that PHA activates sodium-dependent transport of methionine and that this activation is blocked by the folate antagonist, MTX.
Assuntos
Ativação Linfocitária , Linfócitos/metabolismo , Metionina/metabolismo , Metotrexato/farmacologia , Transporte Biológico/efeitos dos fármacos , Humanos , Técnicas In Vitro , Metotrexato/metabolismo , Fito-Hemaglutininas/farmacologiaRESUMO
We report here an evaluation of 55 pregnancies at risk for a sickle hemoglobinopathy prenatally diagnosed by restriction-endonuclease analysis, with the endonucleases MstII and HpaI, of amniocyte DNA. The diagnosis was completed in all cases. Eleven fetuses were predicted to be affected, of which six were terminated. Forty-one of the 55 cases were confirmed. One false-negative was reported in a case predicted to be hemoglobin AS but that was determined to be hemoglobin SS at birth. We estimate that the 55 cases represent only 5% of the pregnancies at risk for a sickle hemoglobinopathy in the New York metropolitan area during the study period. We conclude that the prenatal diagnosis of sickle hemoglobinopathies by molecular methods is reliable. However, the efficiency of utilization and effectiveness of prenatal testing is dependent on the early prospective identification of couples at risk and on the education of communities concerning the significant morbidity of the sickle hemoglobinopathies and the reproductive choices now available to them.