Review
TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?

https://doi.org/10.1016/j.tips.2006.06.007Get rights and content

The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene–drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.

Section snippets

Pharmacogenetic testing for the administration of oncology drugs

Life-threatening toxicity has been a risk of cancer therapy since the development of nitrogen mustards 1, 2. Because most oncology drugs are administered at the maximally tolerated dose for the population and have a narrow therapeutic index, individuals with altered distribution, metabolism or elimination can suffer life-threatening adverse reactions. The identification of patients ‘too ill’ to benefit from therapy [3] and of methods of supportive care 4, 5 has improved safety, but uncommon

TPMT and 6-MP

6-MP is a prodrug; its principal active metabolites, thioguanine nucleotides (TGNs), preferentially kill rapidly growing cells by inhibiting DNA and RNA synthesis. As a cytotoxic agent, 6-MP is more widely used to treat various autoimmune disorders and prevent organ rejection. Similarly, the 6-MP prodrug azathioprine is used to treat rheumatoid arthritis and prevent renal allograft rejection. However, this review (and the FDA consideration of labeling changes for 6-MP) focuses on the treatment

UGT1A1 and irinotecan

Primarily used to treat advanced colorectal cancer, irinotecan is a prodrug that is converted by carboxylesterase-2 to SN-38 [16], the active DNA topoisomerase I inhibitor that mediates the therapeutic and toxic effects of the drug. SN-38 is mostly eliminated by glucuronidation, the enzymatic conjugation of glucuronic acid to form the more water-soluble metabolite SN-38 glucuronide (SN-38G). Patients with the highest SN-38:SN-38G ratios are at increased risk of one of the most common severe

DPYD and 5-FU

For decades, 5-FU has been a staple of therapy for various solid tumors. In 1985, a 27-year-old woman with breast cancer lapsed into a prolonged stuporous state after two cycles of 5-FU-containing chemotherapy [26] and was found to have elevated concentrations of thymidine and uracil in her body fluids. Based on the pattern of these biochemical abnormalities in different family members and the known pathways of pyrimidine salvage, the investigators proposed that a heritable defect in

Current translation of pharmacogenetic research

The comprehensive development of pharmacogenetic tests entails determining the relative contributions of heritable and environmental factors to the therapeutic index of a given drug for individuals in different populations, and prospective confirmation of the use of this information in selecting and dosing therapy [38]. However, genetic tests for a given therapy might benefit patients before this development process is completed. For TPMT–6-MP and UGT1A1–irinotecan, the FDA convened panels of

The future of cancer pharmacogenetics

It is difficult to predict when and how further pharmacogenetic information will be integrated into the routine management of cancer therapy [39] but current trends indicate three important themes during the next five years.

Concluding remarks

Two clinically useful pharmacogenetic tests for anticancer agents are now available to practitioners; how best to use the information generated by these tests remains to be determined. The tests could be used to screen for patients at risk of severe toxicity from 6-MP or irinotecan before the initiation of treatment or to help clinicians decide among management options when unexpected toxicity from these drugs arises. The available data indicate that these tests will not predict toxicity

Acknowledgements

M.L.M. is supported by US National Institute of General Medical Sciences grant T32 GM07019 in clinical therapeutics. More-detailed information about these drugs and related genes can be found on the Pharmacogenetics and Genomics Knowledge Base (http://www.pharmgkb.org/).

References (67)

  • L.O. Jacobson

    Studies on the effect of methyl-bis(β-chloroethyl)amine hydrochloride on neoplastic diseases and allied disorders of the hemopoietic system

    J. Am. Med. Assoc.

    (1946)
  • D.A. Karnofsky et al.

    The clinical evaluation of chemotherapeutic agents in cancer

  • D.W. Maher

    Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial

    Ann. Intern. Med.

    (1994)
  • S. Schimpff

    Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia

    N. Engl. J. Med.

    (1971)
  • W.E. Evans et al.

    Pharmacogenomics – drug disposition, drug targets, and side effects

    N. Engl. J. Med.

    (2003)
  • A.A. Desai

    Pharmacogenomics: road to anticancer therapeutics nirvana?

    Oncogene

    (2003)
  • R.M. Weinshilboum et al.

    Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity

    Am. J. Hum. Genet.

    (1980)
  • L. Lennard

    Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations

    Clin. Pharmacol. Ther.

    (1987)
  • L. Lennard

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

    Clin. Pharmacol. Ther.

    (1989)
  • E. Schaeffeler

    Comprehensive analysis of thiopurine S-methyltransferase phenotype–genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants

    Pharmacogenetics

    (2004)
  • C.R. Yates

    Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance

    Ann. Intern. Med.

    (1997)
  • W.E. Evans

    Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine

    J. Clin. Oncol.

    (2001)
  • R. Humerickhouse

    Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2

    Cancer Res.

    (2000)
  • E. Gupta

    Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea

    Cancer Res.

    (1994)
  • P.J. Bosma

    The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome

    N. Engl. J. Med.

    (1995)
  • L. Iyer

    Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes

    J. Clin. Invest.

    (1998)
  • L. Iyer

    Phenotype–genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism

    Clin. Pharmacol. Ther.

    (1999)
  • Y. Ando

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

    Cancer Res.

    (2000)
  • L. Iyer

    UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity

    Pharmacogenomics J.

    (2002)
  • F. Innocenti

    Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan

    J. Clin. Oncol.

    (2004)
  • M. Tuchman

    Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity

    N. Engl. J. Med.

    (1985)
  • R.B. Diasio

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

    J. Clin. Invest.

    (1988)
  • E.E. Vokes

    Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer

    J. Clin. Oncol.

    (1996)
  • Cited by (76)

    • Translational pharmacogenetics: pharmacogenetically driven clinical decision making

      2021, Principles of Translational Science in Medicine: From Bench to Bedside, Third Edition
    • Mechanisms of cancer stem cell therapy

      2020, Clinica Chimica Acta
      Citation Excerpt :

      The main problem is that all cells in a cancer tumor are assumed to be genetically identical in the genetic analysis of tumors. Pharmacogenomics studies based on the stochastic model are facing problems and obstacles that have been revealed during tests for the approval by the USA Food and Drug Administration (FAD) [9]. Such studies have examined only a few common genetic differences, including thiopurine methyltransferase (TPMT) and trasferaseisoform1A1-uridineglucoronosyl in metabolizing drugs, which are used to predict the toxicity risk for individuals caused by thiopurines and irinotecan, respectively.

    • Pharmacogenomics and personalized medicine in the treatment of human diseases

      2018, Molecular Pathology: The Molecular Basis of Human Disease
    • UDP-Glycosyltransferases

      2018, Comprehensive Toxicology: Third Edition
    • Target Identification and Validation: Translational Pharmacogenetics to Support Pharmacogenetically Driven Clinical Decision Making

      2015, Principles of Translational Science in Medicine: From Bench to Bedside: Second Edition
    View all citing articles on Scopus
    View full text