Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations.
Blood
; 86(2): 677-84, 1995 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-7605998
ABSTRACT
Although dihydrofolate reductase (DHFR) gene amplification is a common mechanism of resistance to methotrexate (MTX) in tumor cell lines, with the exception of a few case reports, the incidence of this phenomenon as a mechanism of MTX resistance in the clinic has not been reported. We studied 38 untreated patients and 29 patients in relapse with acute lymphoblastic leukemia (ALL) for gene amplification and p53 gene mutations. Three patients were studied both at diagnosis and at each of two relapses after treatment with MTX. Nine of 29 relapsed patients (31%) had low-level DHFR gene amplification (two to four gene copies) associated with increased levels of DHFR mRNA and enzyme activity. Of significance was a correlation of gene amplification with p53 mutations in seven of nine relapsed patients (P < .001). Low-level DHFR gene amplification may be an important cause of MTX resistance in ALL and strengthens the concept that mutations in the p53 gene may lead to gene amplification as a consequence of defective cell cycle control.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tetrahidrofolato Deshidrogenasa
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Células Madre Neoplásicas
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Regulación Leucémica de la Expresión Génica
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Amplificación de Genes
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Metotrexato
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Genes p53
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Proteínas de Neoplasias
Límite:
Adolescent
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Adult
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Aged
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Revista:
Blood
Año:
1995
Tipo del documento:
Article
País de afiliación:
Estados Unidos