Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2

Abstract

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…IM is predominantly excreted through the biliary-fecal route 41 and BCRP is highly expressed in the small intestine and bile canaliculi of the liver. 42,43 The presence of BCRP in the small intestine suggests that it contributes to the regulation of substrate uptake from the gastrointestinal tract through back-transport of substrates reentering the gut lumen. Given the fact PA317 cells transfected with ABCG2 421A have reduced BCRP expression compared with wild type, 44 the plasma IM concentration for patients carrying the ABCG2 421C/C genotype is therefore thought to be lower than in those carrying the 421A allele.…”

Insights into the stem cells of chronic myeloid leukemia

“…20,98 Similarly, ABCB1 (MDR) and ABCG2, two genes that encode key transporters that efflux many drugs are expressed at selectively elevated levels on primitive CML cells. 20,104,105 Heightened genomic instability has long been thought to be a feature of CML and in the last decade quantitative measurements have now provided definitive evidence that the BCR-ABL fusion gene markedly enhances the genomic instability in hematopoietic cells. [106][107][108] This property is mediated in concert with elevated levels of reactive oxygen speciesdependent DNA damage that affect the genome broadly, thereby promoting the generation of IM-resistant derivatives.…”

Lack of ABC transporter autoinduction in mice following long-term exposure to imatinib

“…The two ABC transporter proteins implicated in this process, namely ABCB1 (P-glycoprotein, MDR1) and ABCG2 (BCRP, MXR), [8][9][10] are particularly highly expressed in the small intestine, and the bile canaliculi of the liver. 11,12 A previous in vitro study, utilizing human Caco-2 cells as a model of intestinal drug transport, demonstrated that chronic exposure to imatinib was associated with maximal induction of ABCB1 and ABCG2 after 39 days of treatment with 10 μM imatinib, showing 5-fold and 17-fold increases in mRNA, respectively. 13 At this point, intracellular imatinib accumulation was shown to be 2-fold higher in treatment naïve cells as compared to those having been subjected to chronic drug treatment.…”