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 Journal Article

  

Authors:	Goker, E.; Waltham, M.; Kheradpour, A.; Trippett, T.; Mazumdar, M.; Elisseyeff, Y.; Schnieders, B.; Steinherz, P.; Tan, C.; Berman, E.; Bertino, J. R.
Article Title:	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
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. (C) 1995 by The American Society of Hematology.
Keywords:	lymphoma; children; hybridization; cells; intensive therapy; wild-type p53
Journal Title:	Blood
Volume:	86
Issue:	2
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	1995-07-15
Start Page:	677
End Page:	684
Language:	English
ACCESSION:	WOS:A1995RH80100030
PROVIDER:	wos
PUBMED:	7605998
DOI:	10.1182/blood.V86.2.677.bloodjournal862677
Notes:	Article -- Source: Wos

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