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Genetic factors influencing Pyrimidine-antagonist chemotherapy

The Pharmacogenomics Journal volume 5, pages 226–243 (2005)Cite this article

Abstract

Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumour-specific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5′-nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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Abbreviations

AML:

acute myeloid leukaemia

ara-C:

cytarabine

ara-CMP:

cytarabine monophosphate

ara-U:

uracil-arabinoside

BSA:

body surface area

BUP1:

β-ureidopropionase

CDD:

cytidine deaminase

CMF:

cyclophosphamide, methotrexate and 5-fluorouracil

CMP:

deoxycytidine monophosphate

CYP450:

cytochrome P450

CYP1A2:

cytochrome P450 1A2

CYP2A6:

cytochrome P450 2A6

CYP2C8:

cytochrome P450 2C8

dCDP:

deoxycytidine diphosphate

dCK:

deoxycytidine kinase

dCTP:

deoxycytidine triphosphate

dFCR:

5′-deoxy-5-fluorocytidine

dFdC:

gemcitabine

dFdCDP:

gemcitabine diphosphate

dFdCMP:

gemcitabine monophosphate

dFdCTP:

gemcitabine triphosphate

dFdU:

2′-deoxy-2′, 2′-difluorouridine

dFdUMP:

2′-deoxy-2′, 2′-difluorouridine monophosphate

dFUR:

5′-deoxy-5-fluorouridine

DPD:

dihydropyrimidine dehydrogenase

DPYD:

dihydropyrimidine dehydrogenase gene

DPYS:

dihydropyrimidinase

dTMP:

deoxy-thymidine monophosphate

dUMP:

deoxyuridine monophosphate

dUTP:

deoxy-uridine triphosphate

dUTPase:

dUTP nucleotidohydrolase

ECGF:

endothelial cell growth factor

FdUDP:

5-fluoro-deoxy-uridine-diphosphate

FdUMP:

5-fluoro-deoxy-uridine monophosphate

FdUTP:

5-fluoro-deoxy-uridine-triphosphate

5-FU:

5-fluorouracil

FUDP:

5-fluoro-uridine-diphosphate

FUDR:

5-fluoro-deoxy-uridine

FUMP:

5-fluoro-uridine-monophosphate

FUTP:

5-fluoro-uridine-triphosphate

IFN:

interferon

IHC:

immunohistochemistry

LV:

leucovorin

MITO:

mitomycine

MITOX:

mitoxantrone

MRP:

multi-drug resistance protein

MTHFR:

methylene tetrahydrofolate reductase

MTX:

methotrexate

5NT:

5′-nucleotidase

OPRT:

orotate phosphoribosyl transferase

RNR:

ribonucleotide reductase

SNP:

single-nucleotide polymorphism

TK:

thymidine kinase

TP:

thymidine phosphorylase

TS:

thymidine synthase

UDPK:

uridine diphosphate kinase

UK:

uridine kinase

UMPK:

uridine monophosphate kinase

UP:

uridine phosphorylase

USF:

upstream stimulatory factor

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Authors and Affiliations

  1. Department of Pharmacy, Diaconessen Hospital Meppel & Bethesda Hospital Hoogeveen, Meppel, The Netherlands

    J G Maring

  2. Department of Pulmonary Diseases, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands

    H J M Groen & F M Wachters

  3. Department of Pharmacy, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands

    D R A Uges

  4. Department of Medical Oncology, University of Groningen & University Medical Center Groningen, Groningen, The Netherlands

    E G E de Vries

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  1. J G Maring
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  2. H J M Groen
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  3. F M Wachters
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  4. D R A Uges
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  5. E G E de Vries
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Correspondence to J G Maring.

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None declared.

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Maring, J., Groen, H., Wachters, F. et al. Genetic factors influencing Pyrimidine-antagonist chemotherapy. Pharmacogenomics J 5, 226–243 (2005). https://doi.org/10.1038/sj.tpj.6500320

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  • DOI: https://doi.org/10.1038/sj.tpj.6500320

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