Dihydropyrimidine dehydrogenase (DPD) activity in gastric cancer tissue and effect of DPD inhibitory fluoropyrimidines.
BACKGROUND
Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU). The effect of DPD inhibitory fluoropyrimidines (DIF) is presumably related to DPD activity. We studied the efficacy of DIF (tegafur + uracil UFT], tegafur + gimeracil + osteracil [S-1 (TS-1)]) relative to DPD activity, with other fluoropyrimidines as controls.


METHODS
The efficacy of DIF relative to DPD activity was evaluated in 58 gastric cancer patients who received postoperative administration of fluoropyrimidines, consisting of DIF in 42 patients (UFT in 23; S-1 in 19) and non-DIF in 16 patients.


RESULTS
In patients with low DPD activity (under 40 U/mg protein), curative potential tended to be lower for DIF than for non-DIF, but the survival rate was the same for both. In patients with high DPD activity (40 U/mg protein or more), such a tendency was not detected. In a comparison between those treated with UFT and those treated with S-1, prognosis was better in the latter group, in spite of their predominance of lower curative potentials of B or C. In 27 patients with measurable lesions, a partial response (PR) or higher response occurred in 33% (5/15) of those with low DPD activity, and in 17% (2/12) of those with high DPD activity. In the patients with low DPD activity, non-DIF induced no change (NC) in 17% (16), and progressive disease (PD) in the rest. UFF induced PD in all 5 patients, while S-1 induced a response rate of 44% (7/16), with NC in 25% (4/16). In the patients with high DPD activity, on the other hand, non-DIF (n = 3) and UFT (n = 3) induced PD in all the patients, while S-1 induced PR in 33% (2/6) and NC or a higher response in 67% (4/6).


CONCLUSIONS
It is recommended to use S-1 rather than UFF in patients with high DPD activity. Measurement of DPD was useful in drug selection.
Usuki
Hisashi
H
First Department of Surgery, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kagawa 761-0793, Japan.
Ishimura
Ken
K
Yachida
Shinichi
S
Hagiike
Masanobu
M
Okano
Keiichi
K
Izuishi
Kunihiko
K
Karasawa
Yukihiko
Y
Goda
Fuminori
F
Maeta
Hajime
H
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP); D018450:Disease Progression; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007564:Japan; D002955:Leucovorin / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008207:Lymphatic Metastasis; D010088:Oxidoreductases / Q000187:drug effects* / Q000378:metabolism*; D010094:Oxonic Acid / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D013223:Statistics as Topic; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000401:mortality; D016019:Survival Analysis; D005641:Tegafur / Q000627:therapeutic use*; D016896:Treatment Outcome; D014498:Uracil / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D014498:Uracil; D010094:Oxonic Acid; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil