A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform.

Article Details

Citation

Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K, Liewehr DJ, Dahut WL, Miao X, Figg WD

A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform.

Pharmacogenomics J. 2010 Jun;10(3):191-9. doi: 10.1038/tpj.2009.57. Epub 2009 Dec 29.

PubMed ID
20038957 [ View in PubMed
]
Abstract

The anticancer agent docetaxel shows significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also shows wide pharmacological variation. Past pharmacogenetic research has not explained this variation. Patients with prostate cancer enrolled in a randomized phase II trial using docetaxel and thalidomide versus docetaxel alone were genotyped using the Affymetrix DMET 1.0 platform, which tests for 1256 genetic variations in 170 drug disposition genes. Genetic polymorphisms were analyzed for associations with clinical response and toxicity. In all, 10 single-nucleotide polymorphisms (SNPs) in three genes were potentially associated with response to therapy: peroxisome proliferator-activated receptor-delta (PPAR-delta), sulfotransferase family, cytosolic, 1C, member 2 (SULT1C2) and carbohydrate (chondroitin 6) sulfotransferase 3 (CHST3). In addition, 11 SNPs in eight genes were associated with toxicities to treatment: spastic paraplegia 7 (pure and complicated autosomal recessive) (SPG7), CHST3, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6), ATPase, Cu++ transporting, alpha polypeptide (ATP7A), cytochrome P450, family 4, subfamily B, polypeptide 1 (CYP4B1) and solute carrier family 10 (sodium/bile acid cotransporter family), member 2 (SLC10A2). Genotyping results between drug metabolizing enzymes and transporters (DMET) and direct sequencing showed >96% of concordance. These findings highlight the role that non-CYP450 metabolizing enzymes and transporters may have in the pharmacology of docetaxel and thalidomide.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
ThalidomideCytochrome P450 2B6ProteinHumans
No
Substrate
Inducer
Details