Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells

• Published in: European journal of cancer (1990) Vol. 38; no. 9; pp. 1271 - 1277
• Main Authors: Takechi, T, Fujioka, A, Matsushima, E, Fukushima, M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-06-2002; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Dihydropyrimidine dehydrogenase; Dihydrouracil Dehydrogenase (NADP); Drug Interactions; Drug synergism; Enzyme inhibitors for therapeutic use; Fluorouracil - therapeutic use; Fluorouracil pharmacokinetics; Human tumours; In vitro and in vivo antitumour efficacy; Maximum Allowable Concentration; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Oxidoreductases - antagonists & inhibitors; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pharmacology. Drug treatments; Pyridines - therapeutic use; Tumor Cells, Cultured; Enzyme inhibitors for therapeutic use; Human tumours; Fluorouracil pharmacokinetics; Dihydropyrimidine dehydrogenase; In vitro and in vivo antitumour efficacy; Drug synergism; Antineoplastic agent; Human; Cell proliferation; Cell culture; Enzyme; Treatment efficiency; Fluoropyrimidine derivatives; Enzyme inhibitor; ); Dihydropyrimidine dehydrogenase (NADP; Experimental study; In vitro; Optimization; Chemotherapy; Pyrimidine derivatives; Catabolism; Oxidoreductases; Pharmacokinetics; Fluorouracil
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(02)00048-5

The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration–time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51±12%; FT, 21±25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.