Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients

Chew, Sin-Chi; Lim, Joanne Siok Liu; Singh, Onkar; Chen, Xiangai; Tan, Eng‐Huat; Lee, Edmund-J D; Chowbay, Balram

doi:10.1007/s00228-013-1596-3

Cited by 30 publications

(21 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ERCC2 ( ERCC Excision Repair 2 ), a gene involved in repair of DNA damage, was demonstrated to be associated with docetaxel‐induced neutropenia . However, current researches on myelosuppression in Chinese Han population were limited to CYP3A4 , CYP3A5 , ACBC1 and nuclear receptors genes in docetaxel pathway . Therefore, a systematic study with more candidate genes that include additional drug transporter and metabolism genes is useful for probing the underlying mechanism of myelosuppression further.…”

Section: What Is Known and Objectivementioning

confidence: 99%

See 1 more Smart Citation

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

et al. 2019

View full text Add to dashboard Cite

What is known and objective Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single‐nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual‐patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population. Until now, few researches on myelosuppression included Chinese Han patients. In this study, we conducted a systematic study of potential biomarkers for docetaxel‐induced myelosuppression in Han Chinese patients. Methods We examined 61 SNPs in 36 genes that code for drug transporters, metabolism enzymes, nuclear receptors and DNA repair pathway in 110 Chinese Han patients receiving docetaxel‐based chemotherapy. Genotyping was conducted using the Sequenom MassARRAY system. Significant SNPs were identified by logistic regression, and gene‐gene interactions were investigated by generalized multifactor dimensionality reduction (GMDR) analysis. Results and discussion Our results revealed that 11 SNPs in nine genes (SLC15A1, SLCO1A2, CYP2D6, FMO3, UGT1A1, NAT2, SULT2A1, PXR and HNF4α) were associated with docetaxel‐induced myelosuppression. GMDR analyses suggested that a 3‐locus model: SLC15A1 rs2297322—PXR rs3732359—FMO3 rs2266782 was an appropriate predictive model of docetaxel‐induced myelosuppression (P = .017, Testing Bal.Acc = 0.653, CV Consistency = 10/10). What is new and conclusion Our findings suggest multiple novel predictive biomarkers of docetaxel‐induced myelosuppression: SLC15A1 rs2297322, PXR rs3732359 and FMO3 rs2266782. These discoveries should help in advancing future personalized therapy of docetaxel‐based chemotherapy specific to Chinese Han patients.

show abstract

Section: What Is Known and Objectivementioning

confidence: 99%

“…Several single‐nucleotide polymorphisms (SNPs) in relevant genes mentioned above have been associated with docetaxel myelosuppression . However, a number of studies have reported contradictory results that raise questions about the reliability of these biomarkers of docetaxel‐induced ADRs in different patient samples .…”

Section: What Is Known and Objectivementioning

confidence: 99%

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Moreover, endogenous compounds, such as steroid hormones and bile acids, can activate NR1I3 and NR1I2 involved also in various processes, such as cell differentiation and tumorigenesis as well as endocrine homeostasis. 20 In an exploratory study on the influence of regulatory nuclear receptors (NR1I2/pregnane X receptor, NR1I3/CAR, RXRα, and Hepatocyte Nuclear Factor 4 Alpha) on docetaxel pharmacokinetics in Chinese patients with nasopharyngeal cancer, Chew et al 21 identified several genetic variants in NR1I3 potentially related to hematologic toxicity. Furthermore, it has been found that nuclear receptors influenced the regulation at transcriptional level of ADME genes encoding phase I and II and drug transporters, after the activation by ligand binding.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic Variants in NR1I3 and UGT2B7 Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case‐Control Study

Arbitrio

Scionti

Altomare

et al. 2019

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Taxane‐related peripheral neuropathy (TrPN) is a dose‐limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug‐metabolizing enzyme and transporter microarray platform, in a retrospective case‐control study, the correlation between ADME polymorphic variants and grades ≥ 2−3‐TrPN was investigated. In a breast cancer (BC) training set, five single‐nucleotide polymorphisms in NR1I3 and UDP‐glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2−3‐TrPN protection. By receiver operating characteristic curves, the grades ≥ 2−3‐TrPN‐related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel‐TrPN and UGT2B7 to docetaxel‐TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants.

show abstract

“…While some PXR polymorphisms did not seem to interact with cancer growth, progression, or drug response (Justenhoven et al, 2011; Martino et al, 2013; Tham et al, 2007), several others were found to be significantly associated with cancer risk, growth, progression, or therapeutic outcome. For instance, the PXR polymorphisms have been shown to be associated with increased lung cancer risk in smokers (Zhang et al, 2014a) (Zhang et al, 2014b), higher prostate-specific antigen levels in prostate cancer patients (Reyes-Hernandez et al, 2014), lymphoma risk (Campa et al, 2012), pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in breast cancer patients, pharmacokinetics and toxicity of irinotecan in colorectal cancer patients (Mbatchi et al, 2016), risk of colorectal cancer (Andersen et al, 2010), Barrett’s esophagus and esophageal adenocarcinoma (van de Winkel et al, 2011a), and docetaxel disposition in nasopharyngeal cancer patients (Chew et al, 2014). Hence, a complete mapping of PXR polymorphisms is required to fully understand the PXR activation in a variety of tumors.…”

Section: Future Directionsmentioning

confidence: 99%

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

View full text Add to dashboard Cite

Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

show abstract

Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients

Cited by 30 publications

References 48 publications

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

Polymorphic Variants in NR1I3 and UGT2B7 Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case‐Control Study

Pregnane X Receptor and Cancer: Context-Specificity is Key

Contact Info

Product

Resources

About