Up-regulation in dihydropyrimidine dehydrogenase activity by raltitrexed causes antagonism in combination with 5-fluorouracil.

Abstract

BACKGROUND AND 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.

CONCLUSION:

Raltitrexed may up-regulate DPD activity in tumor cells, resulting in antagonism when combined with 5-FU.

• Authors: Yasuhiro Nozoe, Yutaka Ogata, Yasumi Araki, Teruo Sasatomi, Hiroyuki Fukumori, Kazuo Shirouzu
• Journal: Anticancer research (Anticancer Res) 2003 Nov-Dec Vol. 23 Issue 6C Pg. 4663-9 ISSN: 0250-7005 [Print] Greece
• PMID: 14981911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Quinazolines
• RNA, Messenger
• Thiophenes
• Dihydrouracil Dehydrogenase (NADP)
• raltitrexed
• Fluorouracil

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Dihydrouracil Dehydrogenase (NADP) (genetics)
• Fluorouracil (antagonists & inhibitors, pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Nude
• Pancreatic Neoplasms (enzymology, pathology)
• Quinazolines (pharmacology)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Thiophenes (pharmacology)
• Transcription, Genetic (drug effects)
• Transplantation, Heterologous
• Tumor Cells, Cultured