Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity.
To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.
Fujiwara
H
H
Department of Surgery 1, Iwate Medical University, 020-8505, Morioka, Japan.
Terashima
M
M
Irinoda
T
T
Takagane
A
A
Abe
K
K
Nakaya
T
T
Yonezawa
H
H
Oyama
K
K
Takahashi
M
M
Saito
K
K
Takechi
T
T
Fukushima
M
M
Shirasaka
T
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005472:Fluorouracil / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D012334:RNA, Neoplasm / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology*; D005641:Tegafur / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D004338:Drug Combinations; D011725:Pyridines; D012334:RNA, Neoplasm; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil