Pharmacogenetics of genes across the doxorubicin pathway.

INTRODUCTION: A large number of genetic polymorphisms have been reported in the genes that mediate the metabolism, transport and pharmacological activity of doxorubicin. The clinical significance of these is still undergoing evaluation. AREAS COVERED: Doxorubicin is a widely used anticancer drug in the treatment of solid tumors and leukemias. It is a drug characterized by inter-individual variation in pharmacokinetic parameters as well as variation in efficacy and toxicity. It has been hypothesized that variation in genes with a function in doxorubicin pharmacology may contribute to this variation in doxorubicin pharmacology. There is evidence that genetic variants effect the expression of proteins associated with the transport, metabolism and mechanism of action of doxorubicin, and may influence efficacy and toxicity. For example, single nucleotide polymorphisms (SNPs) in the ABCB1 transporter gene have been shown to influence both pharmacokinetics and outcome following doxorubicin chemotherapy. Similar associations have been described for SNPs in the carbonyl reductase (CRB1 and CRB3) genes. EXPERT OPINION: Although a number of studies have reported associations between genetic variants and different aspects of doxorubicin pharmacology, these associations are not consistently observed. While such observations give insights into aspects of doxorubicin pharmacology, based on current data genotyping may be of limited clinical utility.