Analysis of single nucleotide polymorphism C3435T of the multidrug resistance gene MDR1 in acute lymphoblastic leukemia. Int J Oncol 2003 Aug;23(2):509-17
Date
07/10/2003Pubmed ID
12851703Scopus ID
2-s2.0-0345974461 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
Multidrug resistance is an important mechanism responsible for refractoriness of leukemia and worse outcome of patients. Overexpression of the multidrug resistance gene, MDR1, is of prognostic relevance in acute myeloid leukemia, while its role in acute lymphoblastic leukemia (ALL) is still under debate. Single nucleotide polymorphisms (SNP) have been detected in the MDR1 gene. The C3435T polymorphism in this gene seems to have functional and clinical consequences. In the present investigation, we have analyzed the role of the C3435T SNP for drug resistance and prognosis of human ALL. The C3435T SNP was analyzed in 20 T-ALL cell lines and in blood samples from 53 ALL patients and 7 healthy donors. The cell line panel consisted of cell lines not prior exposed in vitro to cytostatic drugs as well as of drug-resistant lines which were selected in vitro by exposure to doxorubicin, vincristine, methotrexate, or hydroxyurea. We have developed a highly sensitive matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based genotyping approach to survey the C3435T SNP. Furthermore, mRNA expression was determined by real time reverse-transcribed polymerase chain reaction and doxorubicin sensitivity by a growth inhibition assay. Surprisingly, we did not find a significant correlation between C3435T homo- or heterozygote genotypes and MDR1 mRNA expression of cell lines or blood samples from patients and healthy donors. Furthermore, there was no relationship between the response of the cell lines to doxorubicin and the C3435T genotypes. Homo- or heterozygosity did not correlate to survival of patients in the Kaplan-Meier analysis. In conclusion, we do not have reason to assume that the C3435T SNP contributes to drug resistance of ALL and prognosis of ALL patients.
Author List
Efferth T, Sauerbrey A, Steinbach D, Gebhart E, Drexler HG, Miyachi H, Chitambar CR, Becker CM, Zintl F, Humeny AMESH terms used to index this publication - Major topics in bold
Antineoplastic AgentsAntineoplastic Combined Chemotherapy Protocols
Asparaginase
Case-Control Studies
Cyclophosphamide
Cytarabine
Daunorubicin
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Female
Genes, MDR
Humans
Hydroxyurea
Male
Mercaptopurine
Methotrexate
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Prednisone
Prognosis
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Tumor Cells, Cultured
Vincristine
