Role of pharmacogenomics in the therapy of cancer (original) (raw)

Pharmacogenetics for individualized cancer chemotherapy

Pharmacology & Therapeutics, 2005

The same doses of medication cause considerable heterogeneity in efficacy and toxicity across human populations. Genetic factors are thought to represent important determinants of drug efficacy and toxicity. Pharmacogenetics focuses on the prediction of the response of tumor and normal tissue to standard therapy by genetic profiling and, thereby, to select the most appropriate medication at optimal doses for each individual patient. In the present review, we discuss the relevance of single nucleotide polymorphisms (SNP) in genes, whose gene products act upstream of the actual drug target sites, that is, drug transporters and drug metabolizing phase I and II enzymes, or downstream of them, that is, apoptosis-regulating genes and chemokines. SNPs in relevant genes, which encode for proteins that interact with anticancer drugs, were also considered, that is, enzymes of DNA biosynthesis and metabolism, DNA repair enzymes, and proteins of the mitotic spindle. A significant body of evidence supports the concept of predicting drug efficacy and toxicity by SNP genotyping. As the efficacy of cancer chemotherapy, as well as the drug-related toxicity in normal tissues is multifactorial in nature, sophisticated approaches such as genome-wide linkage analyses and integrate drug pathway profiling may improve the predictive power compared with genotyping of single genes. The implementation of pharmacogenetics into clinical routine diagnostics including genotype-based recommendations for treatment decisions and risk assessment for practitioners represents a challenge for the future.

Primer on medical genomics. Part XII: Pharmacogenomics--general principles with cancer as a model

Mayo Clinic proceedings, 2004

The Human Genome Project has resulted in a new era in the field of pharmacogenetics in which researchers are rapidly discovering new genetic variation, which may help to explain interindividual variability in drug efficacy and toxicity. Pharmacogenetics is the study of the role of genetic inheritance in individual variation in drug response and toxicity. With the convergence of advances in pharmacogenetics and human genomics, the field of pharmacogenomics has emerged during the past decade. Pharmacogenomics is used to refer to the study of the relationship between specific DNA-sequence variation and drug effect. In few other disciplines of medicine are the clinical examples of pharmacogenetics more striking than in oncology. In this field, treatment of patients with cancer is accomplished primarily through the use of chemotherapeutic drugs that have narrow therapeutic indexes, ie, the difference between the toxic and therapeutic dose is relatively small. In this review, we discuss s...

On the use of pharmacogenetics in cancer treatment and clinical trials

European journal of cancer (Oxford, England : 1990), 2014

There are an increasing number of studies devoted to the identification of associations between anticancer drug efficacy and toxicity and common polymorphisms present in the patients' genome. However, many articles presenting the results of such studies do not bring the simple and necessary background information allowing the evaluation of the relevance of the study, its significance and its potential importance for patients' treatment. This position paper first addresses clinical oncologists with the aim of giving them the basic knowledge on pharmacogenetics and on the potential use of gene polymorphisms as predictive biomarkers in routine and clinical research. A secondary objective is to give molecular biologists some recommendations on how to conceive protocols and how to publish their results when they develop pharmacogenetic studies appended to clinical trials or with autonomous goals.

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...

Pharmacogenetic Application in Personalized Cancer Treatment

Pharmacogenetic is broadly understood as study or clinical testing of genetic variations that contribute to differing response to drugs. In cancer treatment, applications of pharmacogenetic cover three areas: avoidance of adverse drug reaction (ADR), selection of treatment options, and prediction of cancer recurrence. Patients with genetic variations in UGT1A1 and DPYD genes are hypersensitive to Irinotecan and 5-Fluorouracil (5FU) respectively. Therefore, the chance for the patients to suffer from ADR from using those drugs can be predicted a priori by simple genetic tests. Secondly, the efficacy of targeted therapy drugs such as Cetuximab and Erlotinib, or nontargeted agents such as temozolomide and nitrosourea has been influenced by the presence of certain genetic or epigenetic markers in tumors. Lastly, microarray analysis to evaluate 70-gene expression profile in breast cancer samples has been shown in recent studies to predict probability of breast cancer recurrence. Patients whose tumors have been determined to have low probability score based on the gene expression profile may omit chemotherapy altogether, avoiding unnecessary therapeutic side effects. In summary, pharmacogenetic tests help patients, their caregivers, and doctors in deciding the best treatment options with favorable chance of success, as well as saving overall treatment costs.

Pharmacogenetics and pharmacogenomics as tools in cancer therapy

Drug Metabolism and Personalized Therapy, 2016

Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmac...

Basics of cancer pharmacogenomics

Journal of B.U.ON.: official journal of the Balkan Union of Oncology

Significant heterogeneity in the efficacy and toxicity of chemotherapeutic agents is observed across the population. Administration of the same dose of an anticancer drug given to a group of cancer patients results in a range of side effects from unaffected to lethal events. Age, gender, organ function, tumor biology, all are associated with drug response, but genetic differences in drug disposition and drug targets can have great impact on treatment results. The metabolic enzymes and cellular

The basic principals of pharmacogenetics testing in cancer treatment

Hospital Pharmacology - International Multidisciplinary Journal

Introduction: Precision medicine is an approach that considers genetics, environment and lifestyle factors when prevent and treat diff erent diseases. The important part of precision medicine is pharmacogeneticss, a branch of clinical pharmacology that analyzes how genetic makeup aff ects the response to the drugs. Methods: Since oncology is a fi eld of particular interest in precision medicine, this article summarizes the basic principles of pharmacogenetics testing in cancer treatment. Topic: The following topics have been discussed: Samples for pharmacogenetics testing (peripheral blood, tumor biopsy, liquid biopsy), methods in pharmacogenetics testing (conventional hotspot methods and comprehensive genome profi ling), comprehensive genome profi ling (CGP) in clinical settings and oncology therapy in Serbia that depends on genetic testing. Conclusion: Pharmacogenetics testing provides the delivery of safe and effi cient therapy. The usage of CGP methods opens up the possibility for the usage of therapies directed to genetic markers across tumor types. However, this approach needs evaluation through well-designed research projects and clinical trials.