Up-regulation in dihydropyrimidine dehydrogenase activity by raltitrexed causes antagonism in combination with 5-fluorouracil.
METHODS
We have studied the influence of raltitrexed, a specific thymidylate synthase (TS) inhibitor, on dihydropyrimidine dehydrogenase (DPD) activity in cultured cancer cells and in transplanted tumors in nude mice. Further, we investigated the combined effect of raltirexed and 5-fluorouracil (5-FU) on the in vitro anti-tumor effect and its correlation to the DPD activity and mRNA level.


RESULTS
By raltitrexed treatment, the DPD activity and mRNA level were increased in HuTu-80 small intestine carcinoma cells, and in its transplanted tumors. On the other hand, raltitrexed showed no influence on DPD activity in MIAPaCa2 pancreatic carcinoma cells. In the study of cell growth activity, the results showed that in MIAPaCa2, the Combination Index (CI) was 0.57 +/- 0.03, representing a synergistic effect, while in HuTu-80, the CI was 1.26 +/- 0.09, representing an antagonistic effect.


CONCLUSIONS
Raltitrexed may up-regulate DPD activity in tumor cells, resulting in antagonism when combined with 5-FU.
Department of Surgery, Kurume University School of Medicine, 67-Asahi-machi, Kurume-City, Fukuoka, 831-0011, Japan.
Yasuhiro
Y
Nozoe
Yutaka
Y
Ogata
Yasumi
Y
Araki
Teruo
T
Sasatomi
Hiroyuki
H
Fukumori
Kazuo
K
Shirouzu
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005472:Fluorouracil / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013876:Thiophenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D011799:Quinazolines; D012333:RNA, Messenger; D013876:Thiophenes; D042943:Dihydrouracil Dehydrogenase (NADP); C068874:raltitrexed; D005472:Fluorouracil