Elsevier

European Journal of Cancer

Volume 34, Issue 10, September 1998, Pages 1493-1499
European Journal of Cancer

Clinical Oncology Update
Pharmacogenetics and cancer chemotherapy

https://doi.org/10.1016/S0959-8049(98)00230-5Get rights and content

Abstract

Cancer chemotherapy is limited by significant inter-individual variations in responses and toxicities. Such variations are often due to genetic alterations in drug metabolising enzymes (pharmacokinetic polymorphisms) or receptor expression (pharmacodynamic polymorphisms). Pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug responses. The role of polymorphisms in specific enzymes, such as thiopurine S-methyltransferases (TPMT), dihydropyrimidine dehydrogenase (DPD), aldehyde dehydrogenases (ALDH), glutathione S-transferases (GST), uridine diphosphate glucuronosyltransferases (UGTs) and cytochrome P450 (CYP 450) enzymes in cancer therapy are discussed in this review.

Introduction

Inter-subject variability in therapeutic drug responses and drug toxicities is a major problem in clinical practice. Such variability is largely due to genetic factors leading to altered drug metabolism and/or receptor expression[1]. Polymorphisms in drug-metabolising enzymes, which appear to be more extensive than those of receptors[2], result in altered pharmacokinetics of therapeutic agents. Since the discovery of debrisoquine hydroxylase deficiency in the 1970s[3], pharmacogenetic polymorphisms of several drug metabolising enzyme systems have been identified and characterised4, 5, 6, 7. Genetic variations in receptor expression systems, or pharmacodynamic polymorphisms, have been recently identified as major determinants of drug responses8, 9.

The relationship between an individual’s capacity to metabolise environmental carcinogens and other xenobiotics and susceptibility to cancer has been extensively studied10, 11, 12, 13. The applicability of pharmacogenetics in cancer chemotherapy is critical due to the following reasons:

  • 1.

    anticancer agents generally have a narrow margin of safety;

  • 2.

    many of these agents are prodrugs and are biotransformed to active counterparts by enzyme systems that exhibit genetic polymorphisms;

  • 3.

    the active forms are usually also associated with toxicity;

  • 4.

    certain anticancer agents are detoxified by polymorphic enzyme systems; and

  • 5.

    most cancer chemotherapeutic drugs exhibit significant inter-patient variability in pharmacokinetics and toxicity.

This review will focus on the role of genetic polymorphisms of well-known classes of drug-metabolising enzymes in cancer chemotherapy.

Section snippets

Thiopurine S-methyltransferase (TPMT)

TPMT catalyses the S-methylation of 6-mercaptopurine (6-MP) (also formed in vivo from the immunosuppressive prodrug, azathioprine), to form inactive metabolites. This competes with two other pathways of 6-MP metabolism that form inactive 6-thiouric acid and active 6-thioguanine nucleotides (6-TGN), catalysed by xanthine oxidase and hypoxanthine phosphoribosyltransferase (HPRT) enzymes, respectively[14]. 6-MP is commonly used as a component of maintenance therapy in acute lymphoblastic leukaemia

Dihydropyrimidine dehydrogenase (DPD)

DPD catalyses the initial, rate-limiting step in the catabolism of pyrimidines such as thymine and uracil and the fluoropyrimidine, 5-fluorouracil (5-FU). 5-FU is one of the most widely used anticancer agents in the treatment of breast, head and neck and colorectal cancers[32]. However, significant inter-individual variations in 5-FU clearance, tumour response and host toxicity have been reported after 5-FU therapy32, 33, 34. These variations may be due to genetic differences in the activity of

N-acetyltransferases (NAT)

Human acetylation polymorphism has been documented since the 1950s with the observation of slow and fast acetylators of isoniazid[60]. Two NAT genes (NAT1* and NAT2*) have been sequenced and located at distinct loci on chromosome 8, pter-q1161, 62. Substrates of NAT1 include p-aminobenzoic acid and p-aminosalicylic acid and those of NAT2 include isoniazid, procainamide, hydralazine and sulphonamide63, 64, 65. NAT1 was initially believed to be monomorphic, but recent reports indicate that the NAT

Glutathione S-transferases (GST)

GSTs are a superfamily of enzymes that conjugate xenobiotics, such as herbicides, insecticides, carcinogens and anticancer agents (cyclophosphamide) with glutathione80, 81, 82, 83. They have also been shown to play a role in multidrug resistance by direct binding to drugs and/or removing them from cells[84]. Increased levels of GST in tumour cells can contribute to the detoxification of the DNA-alkylating cytotoxic metabolite (phosphoramide mustard) of cyclophosphamide, resulting in the

Aldehyde dehydrogenase (ALDH)

The ALDH family comprises of at least seven members: ALDH1 to ALDH5, betaine aldehyde dehydrogenase (BADH) and succinic semialdehyde dehydrogenase (SSDH)[95]. Genetic polymorphisms have been described in ALDH2, which is involved in the metabolism of alcohol[96]. ALDH1, ALDH2 and SSDH have been reported to oxidise aldophosphamide[95]. ALDH1 variants are prevalent up to 10% in the population[97]. A phenotypic deficiency in the excretion of carboxyphosphamide arising from ALDH polymorphism98, 99

Uridine diphosphate glucuronosyltransferases (UGTs)

UGTs are a superfamily of enzymes that catalyse the transfer of glucuronic acid moiety to a variety of endogenous substrates and xenobiotics102, 103, 104, 105. Two major classes of UGT families have been identified: UGT1 and UGT2. UGT1 family members are formed by alternative splicing of exon 1 with the other exons2, 3, 4, 5, resulting in a conserved carboxyl region. UGT2 isoforms are separate gene products, eight of which have been identified so far103, 104, 105, 106. UGT1 enzymes catalyse the

CYP2D6

The CYP2D6 polymorphism was originally suggested in the inter-subject variations observed in debrisoquine metabolism3, 121. CYP2D6 activity is absent in 5–10% of European and North American Caucasian populations122, 123. Several alleles of CYP2D6 have been described, such as CYP2D6A, CYP2D6B, CYP2D6D, CYP2D6E and CYP2D6T[122]. Correlation of poor metabolism phenotype with CYP2D6 genotypes is being studied extensively for various therapeutic classes124, 125, 126, 127. However, most anticancer

Conclusions

A major problem in cancer pharmacology is the prediction of the outcome of therapy, both in terms of tumour response and host toxicity150, 151. Pharmacogenetic variability in drug metabolising enzyme systems is a major determinant of variations in these outcomes. Unpredictable disposition of drugs may result in an undertreatment failing to provide therapeutic effects, or an overtreatment leading to excessive toxicity[152]. The current practice in oncology is to dose patients based upon height

Acknowledgements

The authors would like to thank M. Mortell and H.Y. Tam for their assistance in the preparation of this manuscript. Supported in part by the Clinical Therapeutics Training grant, National Institutes of Health (T32-GM07019).

References (156)

  • W. Kalow

    Pharmacogenetics: its biological roots and the medical challenge

    Clin Pharmacol Ther

    (1993)
  • H.J. Dengler et al.

    Polymorphisms and deficient drug metabolism as triggers of toxic reactions

    Arzneimitt Forsch

    (1977)
  • U.A. Meyer

    The molecular basis of genetic polymorphisms of drug metabolism

    J Pharm Pharmacol

    (1994)
  • F. Gonzalez et al.

    Pharmacogenetic phenotyping and genotyping: present status and future potential

    Clin Pharmacokin

    (1994)
  • E. Jacqz-Aigain

    Genetic polymorphisms of drug metabolism

    Dev Pharmacol Ther

    (1989)
  • Inaba T, Nebert DW, Burchell B, et al. Pharmacogenetics in clinical pharmacology and toxicology. Can J Physiol...
  • P. Propping et al.

    Genetic variation of CNS receptors—a new perspective for pharmacogenetics

    Pharmacogenetics

    (1995)
  • Boddy AV, Ratain MJ. Pharmacogenetics in cancer etiology and chemotherapy. Clin Cancer Res 1997, in...
  • D.W. Nebert et al.

    Human drug-metabolizing enzyme polymorphisms—effects on risk of toxicity and cancer

    DNA Cell Biol

    (1996)
  • P. Shields

    Pharmacogenetics: detecting sensitive populations

    Environ Health Perspect

    (1994)
  • N. Caporaso et al.

    Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemioloic evidence

    Pharmacogenetics

    (1991)
  • Ikawa S, Uematsu F, Watanabe KI, et al. Assessment of cancer susceptibility in humans by use of genetic polymorphisms...
  • L. Lennard

    The clinical pharmacology of 6-mercaptopurine

    Eur J Clin Pharmacol

    (1992)
  • Zimm S, Collins JM, Riccardi R, et al. Variable oral bioavailability of oral mercaptopurine. Is maintenance...
  • L. Lennard et al.

    Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism

    Clin Pharmacol Ther

    (1989)
  • Krynetski EY, Tai HL, Yates CR, et al. Genetic-polymorphism of thiopurine S-methyltransferase. Clinical importance and...
  • R.M. Weinshilboum et al.

    Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity

    Am J Hum Gen

    (1980)
  • H.L. McLeod et al.

    Thiopurine methyltransferase activity in American white subjects and black subjects

    Clin Pharmacol Ther

    (1994)
  • Chocair PR, Duley JA, Sabbaga E, et al. Fast and slow methylators: do racial differences influence risk of allograft...
  • Jang IJ, Shin SG, Lee KH, et al. Erythrocyte thiopurine methyltransferase activity in a Korean population. Br J Clin...
  • H.L. McLeod et al.

    Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults

    Pharmacogenetics

    (1995)
  • C. Szumlanski et al.

    Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver–erythrocyte correlation and presence of isozymes

    Pharmacogenetics

    (1992)
  • Bergan S, Rugstad HE, Klemetsdal B, et al. Possibilities for therapeutic drug monitoring of azathioprine: 6-thioguanine...
  • L. Lennard et al.

    Red blood cell hypoxanthine phosphoribosyltransferase activity measured using 6-mercaptopurine as a substrate: a population study in children with acute lymphoblastic leukaemia

    Br J Clin Pharmacol

    (1993)
  • Szumlanski C, Otterness D, Her C, Lee D, et al. Thiopurine methyltransferase pharmacogenetics: human gene cloning and...
  • Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic...
  • H.L. Tai et al.

    Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity

    Proc Natl Acad Sci USA

    (1997)
  • R.B. Diasio et al.

    Clinical pharmacology of 5-fluorouracil

    Clin Pharmacokin

    (1989)
  • Milano G, Etienne MC, Cassuto-Viguier E, et al. Influence of sex and age on fluorouracil clearance. J Clin Oncol 1992,...
  • R.B. Diasio et al.

    Dihydropyrimidine dehydrogenase activity and fluorouracil chemotherapy

    J Clin Oncol

    (1994)
  • G. Morrison et al.

    Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe averse reactions to 5-fluorouracil-based chemotherapy

    Oncol Nurs Forum

    (1997)
  • Fleming RA, Milano GA, Gaspard MH, et al. Dihydropyrimidine dehydrogenase activity in cancer patients. Eur J Cancer...
  • Z. Lu et al.

    Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients and clinical implication in 5-fluorouracil chemotherapy

    Cancer Res

    (1993)
  • Z. Lu et al.

    Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy

    Clin Pharmacol Ther

    (1995)
  • Tuchman M, Stoeckeler JS, Kiang DT, et al. Familial pyrimidenemia and pyrimidimuria associated with severe fluorouracil...
  • R.B. Diasio et al.

    Familial deficiency of dihydropyrimidine dehydrogenase—biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity

    J Clin Invest

    (1988)
  • B.E. Harris et al.

    Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase-deficiency—a potentially more common pharmacogenetic syndrome

    Cancer

    (1991)
  • Heggie GD, Sommadosi JP, Cross DS, et al. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma,...
  • A.P. Lyss et al.

    Severe 5-fluorouracil toxicity in a patient with decreased dihydropyrimidine dehydrogenase activity

    Cancer Invest

    (1993)
  • Etienne MC, Lagrange JL, Dassonville O, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients....
  • Cited by (96)

    • Drug-Induced Liver Injury

      2022, Comprehensive Pharmacology
    • 2D Germanane Derivative as a Vector for Overcoming Doxorubicin Resistance in Cancer Cells

      2020, Applied Materials Today
      Citation Excerpt :

      Several mechanisms responsible for a development of the drug resistance have been identified. These include the interpatient differences in drug pharmacokinetics [9, 10], a hypoxic tumour microenvironment affecting the cancer cell sensitivity, [9, 11] and more importantly, the specifics of the cancer cells themselves. [9] Besides other adaptive mechanisms of the cancer cells, the resistance is most frequently mediated by an overexpression of the drug efflux pumps from the ABC protein family.

    • Chemotherapy Resistance

      2018, Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy: Second Edition
    • Pharmacogenomics

      2017, Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting
    View all citing articles on Scopus
    View full text