ABSTRACT
BACKGROUND: Some patients with glioblastoma multiform do not respond to temozolomide even though they have aberrant promoter methylation of the DNA repair enzyme O(6)-methylguanine methyltransferase (MGMT). This suggests that additional factors hamper temozolomide cytotoxicity. We aimed to confirm first that temozolomide is a target for the multidrug resistance transporter MDR1/ABCB1 and second to investigate whether genetic variants of the MDR1 gene are associated with the survival of glioblastoma patients treated with temozolomide. MATERIALS AND METHODS: Temozolomide-mediated cytotoxicity was determined by the colorimetric methyl-thiazol-tetrazolium assay in MDR-expressing and MDR-nonexpressing cell lines. Genotypes of three single nucleotide polymorphisms (SNPs) of the MDR1 gene (C1236T, G2677T, and C3435T), MDR1 mRNA expression levels, and the MGMT promoter methylation status were analyzed in 112 glioblastoma patients who had been treated either by surgery plus radiotherapy alone or by additional temozolomide chemotherapy. RESULTS: In vitro analysis revealed that temozolomide-mediated cytotoxicity is dependent on MDR1 expression. Multivariate analysis of MDR1 genotypes showed that the C/C variant of the exon12 C1236T SNP is predictive for survival of patients treated with temozolomide. This effect was independent of the MGMT methylation status. Patients with the C/C genotype had a 2-year overall survival of 37% compared with 8% and 10% for patients with C/T and T/T genotypes, respectively (P=0.02). No influence was seen in the group of patients with radiotherapy only. CONCLUSION: The genotype of the MDR1 exon12 C1236T SNP is a novel independent predictive factor for outcome of temozolomide treatment in glioblastoma patients.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Brain Neoplasms/diagnosis , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Glioblastoma/diagnosis , Glioblastoma/drug therapy , ATP Binding Cassette Transporter, Subfamily B , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Dacarbazine/therapeutic use , Drug Resistance, Neoplasm/genetics , Female , Gene Frequency , Genotype , Glioblastoma/genetics , Glioblastoma/mortality , Humans , K562 Cells , Male , Middle Aged , Polymorphism, Single Nucleotide/physiology , Prognosis , Temozolomide , Treatment Outcome , Young AdultABSTRACT
The purpose of this study was to determine the intra- and inter-rater reliability of lower extremity girth measurements in patients recovering from anterior cruciate ligament (ACL) reconstructive surgery. Nine subjects, within several months of their surgery, volunteered. Circumferential measurements were taken of the involved and uninvolved legs at the following locations: 15 cm inferior to the joint line; 5, 10 and 15 cm superior to the joint line; at the joint line; and at mid-thigh. All subjects were supine with the knee in extension whilst a specially designed device, formulated to make circumferential measurements at locations around the knee, was applied to the extremity. Three physical therapists each repeated all measurements on two occasions, in random order, during the same test session. Intra-tester intraclass correlation (ICCs) calculated showed high coefficients (0.82-1.0) for both the involved and uninvolved sides for all locations of the measurement. Inter-tester ICCs ranged from 0.72 to 0.97. The measurements established sufficiently high reliability to justify their use both within and between examiners for subjects recovering from surgery of the ACL.
