Changes in thymidylate synthase and its inhibition rate and changes in dihydropyrimidine dehydrogenase after the administration of 5-fluorouracil with cisplatin to nude mice with gastric cancer xenograft SC-1-NU.
BACKGROUND
Although 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (cisplatin) in combination have synergistic cytotoxicity against both murine and human neoplasms, the precise mechanism of the synergism, and the effects on thymidylate synthase and its percent inhibition, and the effects on dihydropyrimidine dehydrogenase (DPD) remained to be elucidated.


METHODS
Experimental chemotherapy was performed using SC-1-NU, a human gastric carcinoma xenograft. SC-1-NU was maintained by serial transplantation in male BALB/c nude mice. The nude mice received various chemotherapeutic regimens consisting of 5-FU and/or cisplatin, with different dosages and periods of administration. After the treatment, we examined the in vivo effects of 5-FU and cisplatin in each regimen on thymidylate synthase and its percent inhibition, and the effects on DPD, in addition to the observation of tumor growth inhibition.


RESULTS
The combined use of 5-FU (20 mg/kg per day) and cisplatin (either 1.5 or 7.5 mg/kg per day) showed a synergistic antitumor effect, regardless of the different doses of cisplatin. The long-term administration of 5-FU significantly increased both total thymidylate synthase and the percent thymidylate synthase inhibition rate. The short-term administration of 5-FU significantly decreased DPD. Nevertheless, these changes showed no relation to the combined use of cisplatin.


CONCLUSIONS
Combined administration of cisplatin with 5-FU did not further increase thymidylate synthase inhibition over that occurring with 5-FU alone, which does not support the hypothesis that cisplatin combined with 5-FU modulates thymidylate synthase inhibition in enhancing the anticancer effect of 5-FU. Changes in DPD after the administration of 5-FU may provide an insight into tumor sensitivity and resistance to 5-FU.
Sakurai
Yoichi
Y
Department of Surgery, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
Uraguchi
Takashi
T
Imazu
Hiroki
H
Hasegawa
Shigeru
S
Matsubara
Toshiki
T
Ochiai
Masahiro
M
Funabiki
Takahiko
T
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000187:drug effects / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil