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Pharmacogenetics and cancer therapy

Nature Reviews Cancer volume 1, pages 99–108 (2001)Cite this article

Key Points

  • The field of pharmacogenetics has gained increased attention, particularly with the recent evidence that essentially every human gene is polymorphic. Polymorphisms in gene products that affect cancer drug metabolism can affect the toxicity or efficacy of anticancer therapy.

  • The 10% of the population harbouring mutant alleles of thiopurine methyltransferase are at increased risk of toxicity and secondary tumours after treatment with thiopurine drugs.

  • Polymorphisms in dihydropyrimidine dehydrogenase can affect the toxicity, and variations in thymidylate synthase can affect the anticancer efficacy, of the drug 5-fluorouracil.

  • A glucuronosyltransferase gene has a variable number of TA repeats in its promoter, which affect the expression levels of the enzyme. An active metabolite of a drug used to treat colon cancer, irinotecan, causes side effects more frequently in patients who have low glucuronosyltransferase on the basis of their promoter TA repeat status.

  • Glutathione transferases, enzymes that detoxify many cancer drugs, are inactivated in up to 50% of some populations.

  • Because oestrogen-replacement therapy in women is associated with a higher risk of endometrial cancer in patients who have a specific genotype in a steroid-metabolizing cytochrome P450, such pharmacogenetic information might assist in prescribing practices for oestrogen medications.

  • The data so far implicating genetic polymorphisms in cancer therapy support a practice of incorporating pharmacogenetic studies in cancer clinical trials.

Abstract

Pharmacogenetics is the study of how genetic variations affect drug response. These variations can affect a patient's response to cancer drugs, for which there is usually a fine line between a dosage that has a therapeutic effect and one that produces toxicity. Gaining better insight into the genetic elements of both the patient and the tumour that affect drug efficacy will eventually allow for individualized dosage determination and fewer adverse effects.

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Figure 1: Relationship between cancer drug dose, antitumour efficacy and toxicity.
Figure 2: Types of polymorphisms that affect drug response.
Figure 3: Population distribution of drug-related polymorphisms.
Figure 4: Thiopurine methyltransferase polymorphisms that affect mercaptopurine therapy.
Figure 5: Polymorphisms that affect response to 5-fluorouracil (5-FU) therapy.
Figure 6: Polymorphisms that affect irinotecan therapy.
Figure 7: A single nucleotide polymorphism in intron 3 of CYP3A5 creates a nonfunctional enzyme.

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Acknowledgements

This work is supported in part by the National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) Pharmacogenetics Research Network and Database, the National Cancer Institute (NCI), an NCI Core Grant, and the American Lebanese Syrian Associated Charities (ALSAC).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, 38105, Tennessee, USA

    Mary V. Relling

  2. University of Tennessee College of Pharmacy, Memphis, 38183, Tennessee, USA

    Mary V. Relling & Thierry Dervieux

Authors
  1. Mary V. Relling
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  2. Thierry Dervieux
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Corresponding author

Correspondence to Mary V. Relling.

Supplementary information

Online tables

Online Table 1 | Common anticancer drugs and specific adverse effects (PDF 34 kb)

Online Table 2 | Examples of tumour genetic alterations associated with cancer drug resistance

Related links

Related links

DATABASES

CancerNet:

breast cancer

colorectal cancer

lymphoblastic leukaemia

myeloblastic leukaemias

 LocusLink:

CAR

carboxylesterase

CYP17

CYP2D6

CYP3A4

CYP3A

CYP3A5

DHFR

DPD

folylpolyglutamate synthase

γ-glutamyl hydrolase

glucocorticoid receptor

GST-A

GST-M1

GST-P1

GSTs

GST-T1

HPRT

MDR1

MRP1

MRP2

MTHFR

N-MYC

p53

SP1

topoisomerase II

TPMT

TS

UGT1A1

vitamin D receptor

 Medscape DrugInfo:

azathioprine

codeine

etoposide

5-fluorouracil

irinotecan

isoniazid

mercaptopurine

methotrexate

morphine

phenobarbital

prednisone

thioguanine

 OMIM:

Gilbert's syndrome

FURTHER INFORMATION

Cancer Genome Anatomy Project

Cancer trials

Human Genome Project Information

National Human Genome Institute

NCBI—SNP database

NIGMS site for the public on pharmacogenetics

Pharmacogenetics Knowledge Base

Pharmacogenetics of Anticancer Agents Research (PAAR) Group

SNP Consortium

Glossary

THERAPEUTIC RANGE

The range of doses associated with a reasonable probability of efficacy with an acceptable probability of toxicity.

ANTHRACYCLINES

A group of natural-product anticancer drugs that intercalate in DNA and inhibit topoisomerase II.

P-GLYCOPROTEIN

A cell membrane-embedded protein transporter, normally localized in epithelial tissues, the overexpression of which is linked to resistance of tumour cells to many natural-product anticancer drugs.

ETOPOSIDE-INDUCED SECONDARY LEUKAEMIAS

Drug-induced acute myeloid leukaemias that are characterized by a short onset time and balanced translocations of DNA.

HAEMOLYSIS

Lysis of red blood cells.

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

An inherited enzyme deficiency associated with adverse drug effects that are precipitated by oxidative stress.

SUCCINYLCHOLINE

A neuromuscular blocking medication that induces paralysis.

GERM-LINE POLYMORPHISM

DNA sequence variation among individuals that is inherited and transmitted from one generation to the next.

CYTOCHROME P450

A member of a superfamily of haem-containing enzymes, most of which are concentrated in the endoplasmic reticulum of liver, where they oxidize small molecules.

PRIMER EXTENSION

A method to assess single nucleotide polymorphisms that is based on the annealing of an oligonucleotide primer immediately adjacent to the variable nucleotide, and addition of a complementary-base-specific labelled nucleotide ('sequencing one base at a time').

INVADER PROBE

A method to assess genetic polymorphisms that uses hybridization and 'invasion' of short DNA probes that hybridize to the target (variable versus wild-type) DNA. This causes the DNA to form a structure that can be recognized by a cleaving enzyme that releases a label for assay read-out.

MICROFLUIDICS

Technology that allows use of very small volumes of reagents, shortening reaction times and facilitating scale-up of molecular methods.

PRODRUG

A chemical with little or no intrinsic pharmacological activity that requires metabolism or biotransformation in order to exert is biological effects.

MYELOSUPPRESSION

Depressed production of blood cells deriving from the myeloid lineage, including platelets, some leukocytes and erythrocytes. Because many anticancer drugs suppress the growth or proliferation of rapidly dividing cells, myelosuppression is a common side effect.

NONSYNONYMOUS SNPS

Coding-region SNPs that change the amino-acid sequence of a protein.

TRANSITION

A type of nucleotide-pair substitution that involves the replacement of a purine with another purine, or of a pyrimidine with another pyrimidine: for example, G with A.

TOPOISOMERASE I

A nuclear protein that facilitates replication and transcription of DNA by cleaving single-strand DNA and thereby relaxing topological stress in supercoiled DNA.

LEUKOPAENIA

Low white blood cell (leukocyte) count.

CONSTITUTIVE ANDROSTANE RECEPTOR

A transcription factor that activates specific metabolic enzymes.

XENOBIOTIC

A foreign compound, not endogenously present in the body.

ELECTROPHILE

An electron-deficient atom or molecule that is drawn to react with electron-donating compounds.

PHARMACODYNAMICS

The relationship between drug concentration (pharmacokinetics) and its biological effects (what the drug does to the body).

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Relling, M., Dervieux, T. Pharmacogenetics and cancer therapy. Nat Rev Cancer 1, 99–108 (2001). https://doi.org/10.1038/35101056

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  • DOI: https://doi.org/10.1038/35101056

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