Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma (original) (raw)
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Background: Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. Objectives: This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. Conclusion: The future of HCC treatment should emphasize on understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC.
Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy
The Pharmacogenomics Journal, 2012
The goal of cancer pharmacogenomics is to obtain benefit from personalized approaches of cancer treatment and prevention. Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and targets, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. Although a considerable amount of new targeted agents have been designed based on a finely understanding of molecular alterations in cancer, a wide gap between pharmacogenomic knowledge and clinical application still persists. This review focuses on the relevance of mutational analyses in predicting individual response to antitumor therapy, in order to improve the translational impact of genetic information on clinical practice.
Anti-Cancer Agents in Medicinal Chemistry, 2010
There is wide interpatient variability in drug response and toxicity to standard doses of most anticancer medications. Genetic polymorphisms in genes encoding metabolic enzymes, receptors and drug transporters targeted by anticancer medications are often found, in part, to be responsible for the observed variability. Approximately 80% of all sequence variations residing in genes is in the form of single nucleotide polymorphisms or SNPs. The location of SNPs can be in the protein coding sequence, regulatory regions or at exon-intron boundaries of genes. Adverse drug reactions resulting from these sequence variations are due to changes in the activity of the encoded protein (in many instances the protein is non-functional) or perturbations in the level of gene expression. The goal of pharmacogenetic testing is to identify genetic polymorphisms that predispose patients to an adverse drug reaction, thereby allowing the health care provider to make informed decisions pertaining to the type of drug, dosage and dosage scheduling to be administered.
Pharmacogenetic And Tumour Drugs
EJIFCC, 2005
One of the main goals to improve chemotherapy in cancer patients is to increase the safety while not reducing the efficacy of therapy. Cancer chemotherapy is mainly empirical with the majority of cytotoxic agents given at a fixed dosage based on either body surface area or weight. These compounds have a narrow therapeutic index, and there is no simple index for monitoring pharmacological effects. Approximately 7% of patients are affected by adverse drug reactions (ADRs), increasing the overall hospital costs by 1.9% and drug costs by 15%. Among other influences, the inter-individual genetic variation has a major impact on drug activity. Genetic variations are the result of multiple mechanisms such as single nucleotide polymorphisms (SNPs) (over 90%), insertion, deletion, tandem repeats and microsatellites. In an attempt to individualize therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) are used in search for answers to the hereditary ba...
Drug metabolism and disposition: the biological fate of chemicals, 2014
Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Because drugs used in HCC therapy (e.g., anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake transporters [organic cation transporter (OCT) 1 and OCT3] and efflux transporters [multidrug resistance 1 (MDR1)/P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, and breast cancer resistance protein (BCRP)], selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding nontumor tissue samples were collected from 24 Japanese patients at the time of surgery. Protein expression was determined by immunohistochemistry. Expression data were correlated with clinico...
Gene Expression Variability in Human Hepatic Drug Metabolizing Enzymes and Transporters
PLoS ONE, 2013
Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.