Pharmacogenetics for individualized cancer chemotherapy

https://doi.org/10.1016/j.pharmthera.2005.02.005Get rights and content

Abstract

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.

Section snippets

Pharmacogenetics and the human genome

It is a well-known clinical observation that the same doses of medication cause considerable heterogeneity in efficacy and toxicity across human populations (Evans & Relling, 1999, Fagerlund & Braaten, 2001). This heterogeneity can lead to unpredictable life-threatening or even lethal adverse effects in small groups of patients (Rothenberg et al., 2001, Sargent et al., 2001). The interindividual variability in drug response cannot satisfactorily be explained by factors such as renal and liver

Types of genetic alterations

Polymorphisms represent common variations in a DNA sequence that may lead to reduced activity of the encoded gene, but in some cases, also to increased activities (Evans & Relling, 1999). Unlike somatic mutations, they are stable and heritable. Polymorphisms include single nucleotide polymorphisms (SNPs), micro- and minisatellites. An SNP represents a single base exchange that may or may not cause an amino acid exchange in the encoded protein. The frequency of SNPs is greater than 1% in a

Multiplicity of mechanisms

As described previously, drug resistance to cytostatic drugs is determined by multiple factors (Efferth et al., 1992, Efferth & Volm, 1993, Volm et al., 1993, Volm et al., 2002a, Volm et al., 2002b, Volm et al., 2004, Verrills & Kavallaris, 2003). Despite the fact that anticancer drugs are extremely divergent in their chemical and physical structures and biological actions, a synopsis of the relevant mechanisms, which influence drug effects, allows to categorize them as to whether they act

Drug pathway profiling

The current candidate gene-based approaches require the a priori knowledge and selection of a small number of candidate genes for hypothesis testing. Complex human disorders such as cancer are caused by multiple genetic factors rather than by single causes. This hampers the reliable prediction of tumor drug response and normal tissue toxicity because the understanding of the precise role of all participating factors is still limited. Genome-wide linkage analyses may be a more systematic

References (289)

  • J.E. Diestra et al.

    Expression of multidrug resistance proteins P-glycoprotein, multidrug resistance protein 1, breast cancer resistance protein and lung resistance related protein in locally advanced bladder cancer treated with neoadjuvant chemotherapy: biological and clinical implications

    J Urol

    (2003)
  • J.T. Drummond et al.

    Cisplatin and adriamycin resistance are associated with MutLalpha and mismatch repair deficiency in an ovarian tumor cell line

    J Biol Chem

    (1996)
  • T. Efferth et al.

    Oxidative stress response of tumor cells: microarray-based comparison between artemisinins and anthracyclines

    Biochem Pharmacol

    (2004)
  • T. Efferth et al.

    Reversal of doxorubicin-resistance in sarcoma 180 tumor cells by inhibition of different resistance mechanisms

    Cancer Lett

    (1993)
  • T. Efferth et al.

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency-type Zurich: a splice site mutation as an uncommon mechanism producing enzyme deficiency

    Blood

    (2004)
  • W.E. Evans et al.

    Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase deficient child with acute lymphoblastic leukaemia

    J Pediatr

    (1991)
  • A.A. Ferrando et al.

    Gene expression profiling in T-cell acute lymphoblastic leukemia

    Semin Hematol

    (2003)
  • Z.I. Goldberg et al.

    Role of a DT-diaphorase mutation in the response of anal canal carcinoma to radiation, 5-fluorouracil, and mitomycin C

    Int J Radiat Oncol Biol Phys

    (1998)
  • F.J. Gonzalez et al.

    Evolution of the P450 gene superfamily: animal–plant ‘warfare’, molecular drive and human genetic differences in drug oxidation

    Trends Genet

    (1990)
  • C.F. Higgins et al.

    Is the multidrug transporter a flippase?

    Trends Biochem Sci

    (1992)
  • L.J. Hofseth et al.

    p53: 25 years after its discovery

    Trends Pharmacol Sci

    (2004)
  • J.M. Allan et al.

    Mammalian 3-methyladenine DNA glycosylase protects against toxicity and clastogenicity of certain chemotherapeutic DNA cross-linking agents

    Cancer Res

    (1998)
  • J.M. Allan et al.

    Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

    Proc Natl Acad Sci U S A

    (2001)
  • S. Alves et al.

    Thiopurine methyltransferase pharmacogenetics: alternative molecular diagnosis and preliminary data from Northern Portugal

    Pharmacogenetics

    (1999)
  • C.B. Ambrosone et al.

    Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer

    Cancer Res

    (2001)
  • M.M. Ameyaw et al.

    MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity

    Pharmacogenetics

    (2001)
  • G. Anderer et al.

    Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia

    Pharmacogenetics

    (2000)
  • Y. Ando et al.

    Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis

    Cancer Res

    (2000)
  • Y. Ando et al.

    Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide

    Cancer Biol Ther

    (2002)
  • R. Aplenc et al.

    CYP3A genotypes and treatment response in paediatric acute lymphoblastic leukaemia

    Br J Haematol

    (2003)
  • M. Baekelandt et al.

    Expression of apoptosis-related proteins in an independent determination of patient prognosis in advanced ovarian cancer

    J Clin Oncol

    (2000)
  • K.W. Barbour et al.

    A naturally occurring tyrosine to histidine replacement at residue 33 of human thymidylate synthase confers resistance to 5-fluoro-2′-deoxyuridine in mammalian and bacterial cells

    Mol Pharmacol

    (1992)
  • M. Belanich et al.

    Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain patients treated with carmustine

    Cancer Res

    (1996)
  • L. Bellincampi et al.

    Glutathione transferase P1 polymorphism in neuroblastoma studied by endonuclease restriction mapping

    Clin Chem Lab Med

    (2001)
  • E. Beutler et al.

    Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?

    Proc Natl Acad Sci U S A

    (1998)
  • A.L. Borresen-Dale

    TP53 and breast cancer

    Human Mutat

    (2003)
  • G. Bosson

    Reduced folate carrier: biochemistry and molecular biology of the normal and methotrexate-resistant cell

    Br J Biomed Sci

    (2003)
  • D. Botstein et al.

    Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease

    Nat Genet

    (2003)
  • C. Botti et al.

    Altered expression of FAS system is related to adverse clinical outcome in stage I–II breast cancer patients treated with adjuvant anthracycline-based chemotherapy

    Clin Cancer Res

    (2004)
  • O. Bruserud et al.

    Effects of interleukin 10 on blast cells derived from patients with acute myelogenous leukemia

    Leukemia

    (1995)
  • C.S. Carlson et al.

    Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans

    Nat Genet

    (2003)
  • C.L. Chen et al.

    Simultaneous characterization of glutathione S-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks

    Pharmacogenetics

    (1996)
  • J. Chen et al.

    Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer

    Cancer Epidemiol Biomark Prev

    (2003)
  • V. Cohen et al.

    Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy

    Clin Cancer Res

    (2003)
  • E.S. Collie-Duguid et al.

    Known variant DPYD alleles do not explain DPD deficiency in cancer patients

    Pharmacogenetics

    (2000)
  • S. Conrad et al.

    Identification of human multidrug resistance protein 1 (MRP1) mutations and characterization of a G671V substitution

    J Hum Genet

    (2001)
  • P. Cortazar et al.

    Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer

    J Clin Oncol

    (1999)
  • S.A. Coulthard et al.

    A comparison of molecular and enzyme-based assays for the detection of thiopurine methyltransferase mutations

    Br J Haematol

    (2000)
  • Y. Dai et al.

    Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents

    Curr Oncol Rep

    (2004)
  • D. Dai et al.

    Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid

    Pharmacogenetics

    (2001)
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