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


CONCLUSIONS
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.
Terashima
Masanori
M
First Department of Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Fujiwara
Hisataka
H
Takagane
Akinori
A
Abe
Kaoru
K
Irinoda
Takashi
T
Nakaya
Tsutomu
T
Yonezawa
Hitoshi
H
Oyama
Kenichi
K
Saito
Kazuyoshi
K
Kanzaki
Norio
N
Ohtani
Satoshi
S
Nemoto
Tsuyoshi
T
Hoshino
Yutaka
Y
Kogure
Michihiko
M
Gotoh
Mitsukazu
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D042943:Dihydrouracil Dehydrogenase (NADP); D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005743:Gastrectomy; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D010088:Oxidoreductases / Q000187:drug effects* / Q000378:metabolism*; D010094:Oxonic Acid / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary; D011237:Predictive Value of Tests; D011725:Pyridines / Q000627:therapeutic use; D012189:Retrospective Studies; D013223:Statistics as Topic; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D005641:Tegafur / Q000627:therapeutic use; D013939:Thymidine Phosphorylase / Q000187:drug effects* / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000187:drug effects* / Q000378:metabolism*; D016896:Treatment Outcome; D014498:Uracil / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil