RRC ID 41886
Author Terashima M, Fujiwara H, Takagane A, Abe K, Irinoda T, Nakaya T, Yonezawa H, Oyama K, Saito K, Kanzaki N, Ohtani S, Nemoto T, Hoshino Y, Kogure M, Gotoh M.
Title Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer.
Journal Gastric Cancer
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 1M 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.
Volume 6 Suppl 1
Pages 71-81
Published 2003
PMID 12775024
MeSH Adult Aged Aged, 80 and over Animals Antimetabolites, Antineoplastic / therapeutic use* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Chemotherapy, Adjuvant Combined Modality Therapy Dihydrouracil Dehydrogenase (NADP) Drug Combinations Female Fluorouracil / therapeutic use* Gastrectomy Humans Japan Liver Neoplasms / drug therapy Liver Neoplasms / secondary Lymphatic Metastasis Male Mice Mice, Inbred BALB C Middle Aged Multivariate Analysis Neoplasm Staging Oxidoreductases / drug effects* Oxidoreductases / metabolism* Oxonic Acid / therapeutic use Peritoneal Neoplasms / drug therapy Peritoneal Neoplasms / secondary Predictive Value of Tests Pyridines / therapeutic use Retrospective Studies Statistics as Topic Stomach Neoplasms / enzymology* Stomach Neoplasms / mortality Stomach Neoplasms / therapy* Survival Analysis Tegafur / therapeutic use Thymidine Phosphorylase / drug effects* Thymidine Phosphorylase / metabolism* Thymidylate Synthase / drug effects* Thymidylate Synthase / metabolism* Treatment Outcome Uracil / therapeutic use
IF 5.554
Human and Animal Cells