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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1229–1239 | Cite as

ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer

  • Takehiro Uemura
  • Tetsuya OguriEmail author
  • Ken Maeno
  • Kazuki Sone
  • Akira Takeuchi
  • Satoshi Fukuda
  • Eiji Kunii
  • Osamu Takakuwa
  • Yoshihiro Kanemitsu
  • Hirotsugu Ohkubo
  • Masaya Takemura
  • Yutaka Ito
  • Akio Niimi
Original Article

Abstract

Purpose

ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC).

Methods

Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected.

Results

There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group.

Conclusions

These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.

Keywords

ABCC11/MRP8 5-fluorouracil (5-FU) S-1 Single-nucleotide polymorphism (SNP) Thymidylate synthase (TS) 

Notes

Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (MEXT/JSPSKAKENHI23591156).

Compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

280_2019_3959_MOESM1_ESM.pptx (43 kb)
Supplementary material 1 (PPTX 42 kb)
280_2019_3959_MOESM2_ESM.pptx (63 kb)
Supplementary material 2 (PPTX 62 kb)
280_2019_3959_MOESM3_ESM.docx (17 kb)
Supplementary material 3 (DOCX 17 kb)
280_2019_3959_MOESM4_ESM.docx (15 kb)
Supplementary material 4 (DOCX 15 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Takehiro Uemura
    • 1
    • 2
  • Tetsuya Oguri
    • 3
    Email author
  • Ken Maeno
    • 1
  • Kazuki Sone
    • 1
  • Akira Takeuchi
    • 1
  • Satoshi Fukuda
    • 1
  • Eiji Kunii
    • 4
  • Osamu Takakuwa
    • 1
  • Yoshihiro Kanemitsu
    • 1
  • Hirotsugu Ohkubo
    • 1
  • Masaya Takemura
    • 1
  • Yutaka Ito
    • 1
  • Akio Niimi
    • 1
  1. 1.Department of Respiratory Medicine, Allergy and Clinical ImmunologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
  2. 2.Department of Thoracic OncologyAichi Cancer Center HospitalNagoyaJapan
  3. 3.Education and Research Center for Community MedicineNagoya City University Graduate School of Medical SciencesNagoyaJapan
  4. 4.Department of Respiratory MedicineNagoya City West Medical CenterNagoyaJapan

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