Gastric Cancer

, Volume 6, Supplement 1, pp 71–81

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer

  • Masanori Terashima
  • Hisataka Fujiwara
  • Akinori Takagane
  • Kaoru Abe
  • Takashi Irinoda
  • Tsutomu Nakaya
  • Hitoshi Yonezawa
  • Kenichi Oyama
  • Kazuyoshi Saito
  • Norio Kanzaki
  • Satoshi Ohtani
  • Tsuyoshi Nemoto
  • Yutaka Hoshino
  • Michihiko Kogure
  • Mitsukazu Gotoh
Article

DOI: 10.1007/s10120-003-0221-z

Cite this article as:
Terashima, M., Fujiwara, H., Takagane, A. et al. Gastric Cancer (2003) 6(Suppl 1): 71. doi:10.1007/s10120-003-0221-z

Abstract

Background

This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU).

Methods

A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1 M tegafur — 0.4 M 5-chloro-2,4-dihydroxypyridine — 1 M potassium oxonate (S-1 [TS-1®]) were also compared, using three human gastric cancer xenografts in nude mice.

Results

There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity.

Conclusion

DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.

Key words

Fluoropyrimidines Thymidylate synthase Dihydropyrimidine dehydrogenase Thymidine phosphorylase Gastric cancer 
Download to read the full article text

Copyright information

© International and Japanese Gastric Cancer Associations 2003

Authors and Affiliations

  • Masanori Terashima
    • 1
  • Hisataka Fujiwara
    • 2
  • Akinori Takagane
    • 2
  • Kaoru Abe
    • 2
  • Takashi Irinoda
    • 2
  • Tsutomu Nakaya
    • 2
  • Hitoshi Yonezawa
    • 2
  • Kenichi Oyama
    • 2
  • Kazuyoshi Saito
    • 2
  • Norio Kanzaki
    • 1
  • Satoshi Ohtani
    • 1
  • Tsuyoshi Nemoto
    • 1
  • Yutaka Hoshino
    • 1
  • Michihiko Kogure
    • 1
  • Mitsukazu Gotoh
    • 1
  1. 1.First Department of SurgeryFukushima Medical UniversityFukushimaJapan
  2. 2.First Department of SurgeryIwate Medical UniversityMoriokaJapan

Personalised recommendations