Predicting drug response and toxicity based on gene polymorphisms

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Abstract

The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.

Introduction

The sequencing of the human genome and the development of DNA analysis techniques have allowed considerable progress in pharmacological research. A domain which was growing relatively slowly, pharmacogenetics, suddenly emerged as an autonomous discipline, able to bring a complete renewal in the prescription of chemotherapy, whereas a new domain in oncology, pharmacogenomics, which appeared at the turn of the century, is going to allow the discovery of a number of new potential targets and, as a consequence, of new anticancer drugs. We feel, contrarily to several authors, that there is a clear distinction between these two fields: pharmacogenetics study the role of patient's individual variability on the activity, toxicity or kinetics of given drugs, whereas pharmacogenomics study the function of the genome (especially the tumour genome) on the activity of anticancer drugs. Whereas the former is interested in patient's variability (one drug, many genomes), the latter is interested in drug variability (many drugs, one genome) [1]. As a consequence, pharmacogenetics will allow to adapt the treatments to the genetic characteristics of the patients, while pharmacogenomics will allow to discover new tumour-selective drugs and to adapt the treatments to the genetic characteristics of the tumours.

In this review, we would like to focus on the recent developments of pharmacogenetics in oncology and show how this can lead to a complete renewal in the way the drugs are prescribed in oncology, by taking into account the polymorphisms of the genes encoding proteins involved in drug absorption, metabolism, distribution and elimination, as well as those directly involved in drug action (drug targets) or in the repair of drug-induced lesions. Several reviews in this field have already been published [2], [3], [4].

Gene polymorphisms have been the matter of much research in oncology, and cancer risk appears to strongly depend upon the genetic background of the individuals exposed to the same carcinogenic environment. Molecular epidemiology emerged as a new discipline during the 1990s and is rapidly growing. This review maintains a distinction between the genetic determinants of cancer risk and the genetic determinants of drug action, even if the same genes are sometimes involved, since the same enzymes can be used to detoxify xenobiotics from the environment (and participate to the modulation of cancer risk) and to detoxify a drug administered to treat cancer (and participate to the modulation of drug efficacy). It is also necessary to maintain a distinction between the polymorphisms which are predictive of the aggressiveness of the disease and behave as global prognosis factors, from those which are predictive of drug long-term effects, even if the same end-point (overall survival) is used to evaluate the functional role of these polymorphisms. A review on this topics can be found under Ref. [5].

Whereas several paradigmatic polymorphisms at the level of cytochromes P450 had been discovered and studied long ago by cardiovascular or neuro-pharmacologists, they appeared to play no major role in oncology, and, for a long time, the only relevant polymorphism that had been described in oncology concerned thiopurine methyltransferase (TPMT), an enzyme involved in the detoxification of two drugs used in maintenance treatment of acute leukaemias in children. However, in the past 3 years, a number of enzymes involved in the activity of several anticancer drugs were shown to present functional polymorphisms and there is an exponentially growing number of papers published in this field.

Section snippets

Enzymes involved in the activity of antimetabolites

Antimetabolites constitute a wide family of anticancer drugs which are characterised by the existence of specific enzymatic activation and for inactivation pathways which govern their availability at the level of their target. In addition, most of them have an enzyme as a target; there is consequently a large number of possible functional polymorphisms which may intervene on the toxicity and/or the efficacy of these drugs.

Cytochromes P450

The super-family of cytochromes P450 is involved in the detoxification of many xenobiotics, and in the phase I metabolism of many drugs. Some isoenzymes are responsible for the activation of pro-carcinogens into ultimate carcinogens, especially in the polyaromatic hydrocarbon series. This introduces a confounding factor between cancer risk, cancer prognosis and tumour response to treatment. Many cytochromes P450 are subject to genetic polymorphisms with functional consequences and a complete

Carboxylesterases

Carboxylesterases have not been extensively studied as drug metabolism enzymes and much remains to be done from a pharmacogenetic point of view. One of them, CES2, is responsible for the activation of irinotecan into SN-38 and displays low efficiency towards this substrate [101]. Several SNPs have been identified, some of them located in exons, but none could lead to an amino acid change [102], [103], [104]. A polymorphism located in the promoter region of the gene (−363C>G, allele frequency:

N-Acetyltransferases

Two enzymes are able to catalyse N-acetyl transfer (NAT) reactions, NAT1 and NAT2. The NAT2 gene is subject to extensive polymorphism, but not the NAT1 gene. Several NAT2 alleles leading to the loss of catalytic activity have been identified, corresponding to a phenotype of “slow acetylation” present in 50% of Caucasians. One of the results of this polymorphism is the toxic risk of isoniazide administration [105]. The role of NAT2 on carcinogen activation or detoxification may render these

Glutathione S-transferases

This class of enzymes is involved in the detoxification of many xenobiotics, including anticancer drugs, and the polymorphisms encountered in the various enzymes may be both associated with a modification in cancer risk and in the efficacy of anticancer treatments [108]. These enzymes catalyse the conjugation of a glutathione moiety with electrophilic, hydrophobic compounds, in order to increase their water solubility and facilitate their excretion. They also appear able to detoxify the free

UDP-glucuronosyltransferases (UGT)

This is also an important class of phase II detoxifying enzymes, with many isoforms. UGT1A1 is the main enzyme responsible for bilirubin conjugation to glucuronic acid. Apart from the metabolic diseases accompanying complete defect of the protein (Crigler–Najjar disease), there are several polymorphisms leading to decreased enzyme activity. The UGT1A1*28 polymorphism is characterised by a sequence variation in the gene promoter: there is a 7-TA repeat in the TATA box instead of a 6-TA repeat.

Sulphotransferases

Sulphotransferases are a family of enzymes able to add a sulphate group for the detoxification of xenobiotics and endogenous compounds. Among 11 known members of the SULT gene family, SULT1A1 catalyses the sulphation of a variety of phenolic and oestrogenic compounds, including the active tamoxifen analogue, 4-hydroxy-tamoxifen. A frequent polymorphism (638G>A, arg213his, allele frequency: 35%) has been shown to be associated with low enzyme activity and significant decrease in survival in

DNA repair enzymes

The ability to repair damaged DNA may considerably differ between individuals and is due to a difference in the efficiency of repair systems that are specifically triggered depending on the type of DNA lesions. This discrepancy has been linked to a variability in the genes involved in DNA repair pathways. We would like to present here the genetic polymorphisms of DNA repair genes that have been identified to date (Table 6) and that may play a role in the individual variability of DNA repair,

ABC transporters

ATP-Binding Cassette (ABC) transporters constitute a super-family of proteins able to transport a variety of endogenous or exogenous compounds using the energy provided by ATP hydrolysis. Our knowledge on ABC transporters originates from the identification of P-glycoprotein (ABCB1, the product of the multidrug resistance 1 (MDR1) gene, in cancer cells rendered resistant to a variety of anti-tumour alkaloids and antibiotics. A total of 48 ABC transporters have been identified, but only some of

p53 protein

p53 appears as the most frequently mutated protein in human cancers. Activation of p53 following exposure to cell stress leads to cell cycle arrest and/or apoptosis [266]. The loss of p53 function by oncogenic mutations provides cancer cells with an opportunity to exacerbate their genetic instability and, hence, their tumourigenic and invasive properties [267]. p53 is especially involved in response to DNA-damaging anticancer agents and TP53 mutations lead to the loss of apoptosis induced by

Conclusions and perspectives

In addition to the continuous discovery and development of anticancer drugs aimed at cancer cell killing, new therapeutic approaches are being developed, targeting the very mechanisms of oncogenesis and cancer cell dissemination. A great number of proteins are involved in the mechanism of action of these so-called “targeted therapies” and there is no doubt that an even larger number of polymorphisms playing a crucial role in their activity will be discovered.

A paradigmatic target for these new

Reviewers

Timothy W. Gant, Ph.D., Group Leader, Genomics, Medical Research Council Toxicology Unit, Hodgkin Building, University of Leicester, P.O. Box 138, Lancaster Road, Leicester, LE1 9HN, UK.

Dr. Peter R. Blower, Poole House, Great Yeldham, Halstead, Essex CO9 4HP, UK.

Jacques Robert, M.D., Ph.D., obtained his degrees at the University Louis Pasteur, Strasbourg. He moved to Bordeaux in 1978 to set up a laboratory dedicated to the study of anticancer drug pharmacology. He is presently professor of Experimental Oncology at the University Victor Segalen, Bordeaux, and head of the Pharmacology Department of Institut Bergonié, the comprehensive cancer centre of Bordeaux. He is president of the French Cancer Society and officer of the Pharmacology and Metabolism

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    Jacques Robert, M.D., Ph.D., obtained his degrees at the University Louis Pasteur, Strasbourg. He moved to Bordeaux in 1978 to set up a laboratory dedicated to the study of anticancer drug pharmacology. He is presently professor of Experimental Oncology at the University Victor Segalen, Bordeaux, and head of the Pharmacology Department of Institut Bergonié, the comprehensive cancer centre of Bordeaux. He is president of the French Cancer Society and officer of the Pharmacology and Metabolism group of the European Organisation for Research and Treatment of Cancer (EORTC PAMM Group). The main interests of the group lie in the field of clinical, cellular and molecular pharmacology of anticancer drugs, with special emphasis on the molecular determinants of drug activity and toxicity in patients.

    Valérie Le Morvan, Ph.D., is biologist at Institut Bergonié, in charge of pharmacogenetic and genomic studies in relation with colorectal cancers.

    Denis Smith, M.D., B.Sc., was trained in gastro-enterology and oncology and is currently medical oncologist at Hôpital Saint-André, more specifically in charge of the cancers of the digestive tract.

    Philippe Pourquier, Ph.D., defended his Ph.D. thesis in the laboratory of Jacques ROBERT and spent than 5 years at the laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, USA. He is presently research investigator at the National Institute for Health and Medical Research.

    Jacques Bonnet, Ph.D., is currently professor of Biochemistry and Molecular Biology at the University Victor Segalen Bordeaux 2.

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