Dataset Information

Pharmacogenetic pathway analysis of docetaxel elimination.

ABSTRACT: The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). An analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.

SUBMITTER: Baker SD

PROVIDER: S-EPMC4612590 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacogenetic pathway analysis of docetaxel elimination.

Baker S D SD Verweij J J Cusatis G A GA van Schaik R H RH Marsh S S Orwick S J SJ Franke R M RM Hu S S Schuetz E G EG Lamba V V Messersmith W A WA Wolff A C AC Carducci M A MA Sparreboom A A

Clinical pharmacology and therapeutics 20080528 2

The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP ...[more]

PMID: 18509327

Similar Datasets

Project description:Neoadjuvant chemotherapy has been shown to be equivalent to post-operative treatment for breast cancer, and allows for assessment of chemotherapy response. In a pilot trial of docetaxel (T) and capecitabine (X) neoadjuvant chemotherapy for Stage II/III BC, we assessed correlation between baseline gene expression and tumor response to treatment, and examined changes in gene expression associated with treatment. Patients received four cycles of TX. Tumor tissue obtained from Mammotome core biopsies pretreatment (BL) and post-cycle 1 (C1) of TX was FLash frozen and stored at -70 degrees C until processing. Gene expression analysis utilized Affymetrix HG-U133 Plus 2.0 GeneChip arrays. Statistical analysis was performed using BRB Array Tools after RMA normalization. Gene ontology (GO) pathway analysis used random variance t tests with a significance level of P\0.005. For gene categories identified byGO pathway analysis as significant, expression levels of individual genes within those pathways were compared between classes using univariate t tests; those genes with significance level of P\0.05 were reported. PAM50 analyses were performed on tumor samples to investigate biologic subtype and risk of relapse (ROR). Using GO pathway analysis, 39 gene categories discriminated between responders and non-responders,most notably genes involved in microtubule assembly and regulation. When comparing pre- and post-chemotherapy specimens, we identified 71 differentially expressed gene categories, including DNA repair and cell proliferation regulation. There were 45 GO pathways in which the change in expression after one cycle of chemotherapy was significantly different among responders and nonresponders. The majority of tumor samples fell into the basal like and luminal B categories. ROR scores decreased in response to chemotherapy; this change was more evident in samples from patients classified as responders by clinical criteria. GO pathway analysis identified a number of gene categories pertinent to therapeutic response, and may be an informative method for identifying genes important in response to chemotherapy. Larger studies using the methods described here are necessary to fully evaluate gene expression changes in response to chemotherapy.

Dataset Information

Pharmacogenetic pathway analysis of docetaxel elimination.

Publications

Pharmacogenetic pathway analysis of docetaxel elimination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets