PURPOSE: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values. EXPERIMENTAL DESIGN: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing. RESULTS: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (chi2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome. CONCLUSIONS: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.
PURPOSE:P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancerpatients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values. EXPERIMENTAL DESIGN: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing. RESULTS: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (chi2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome. CONCLUSIONS: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.
Authors: Koji Matsuo; Michele L Eno; Edward H Ahn; Mian M K Shahzad; Dwight D Im; Neil B Rosenshein; Anil K Sood Journal: Am J Clin Oncol Date: 2011-10 Impact factor: 2.339
Authors: Honglin Song; Estrid Hogdall; Susan J Ramus; Richard A Dicioccio; Claus Hogdall; Lydia Quaye; Valerie McGuire; Alice S Whittemore; Mitul Shah; David Greenberg; Douglas F Easton; Susanne Kruger Kjaer; Paul D P Pharoah; Simon A Gayther Journal: Clin Cancer Res Date: 2008-02-15 Impact factor: 12.531
Authors: Andrea Mann; Estrid Hogdall; Susan J Ramus; Richard A DiCioccio; Claus Hogdall; Lydia Quaye; Valerie McGuire; Alice S Whittemore; Mitul Shah; David Greenberg; Douglas F Easton; Bruce A J Ponder; Susanne Krüger Kjaer; Simon A Gayther; Deborah J Thompson; Paul D P Pharoah; Honglin Song Journal: Eur J Cancer Date: 2008-08-22 Impact factor: 9.162
Authors: Uchenna O Njiaju; Eric R Gamazon; Lidija K Gorsic; Shannon M Delaney; Heather E Wheeler; Hae Kyung Im; M Eileen Dolan Journal: Pharmacogenet Genomics Date: 2012-07 Impact factor: 2.089